Process for the preparation of carbapenem intermediates

ABSTRACT

A process for the preparation of a 4-[3-carboxy-3-diazo-2-oxopropyl]azetidin-2-one of the formula &lt;IMAGE&gt;   comprising reacting a 4-acetoxy-2-azetininone of the formula   &lt;IMAGE&gt;  with a compound of the formula   &lt;IMAGE&gt;  in an inert solvent, in the presence of a base and of a silylating agent, in a one-pot process. Many of the products are new. The products are useful in the synthesis of carbapenem antibiotics.

The invention relates to a new process for the preparation of 4-[3-carboxy-3-diazo-2-oxopropyl]azetidin-2-ones which are important intermediates for the synthesis of carbapenem antibiotics and some of which are known.

It is known that 4-acetoxyazetidinones react with trimethylsilyl enol ethers in the presence of Lewis acids to give the corresponding C-C-linked 4-[3-carboxy-3-diazo-2-oxopropyl]azetidin-2-ones (compare European Patent Application No. 78026; J. D. Buynak et al., J. Chem. Soc., Chem. Commun. 1984, 948). This entails the separate and very elaborate preparation of the trimethylsilyl enol ethers used in each case. Since to date in their preparation organometallic bases, such as n-butyllithium or lithium diisopropylamide, have been used, these methods of preparation cannot be combined with the most important and most frequently used carbapenem ester protective group, the 4-nitrobenzyl ester. In addition, to date only zinc (II) halides have been used as Lewis acids in the linkage of diazoenol ethers. Heterogeneous reactions of this type in some cases require elevated reaction temperatures and long reaction times (compare European Patent Application No. 78,026; J. D. Buynak, J. Chem. Soc., Chem. Commun. 1984, 948; P. J. Reider et al., Tetrahedron Lett. 1982, 379), which, as is well known, can have very disadvantageous effects because of the sensitivity of the products.

In addition, it is known that for the reaction to succeed in most cases preceding and separate incorporation of a N-protective group is necessary (compare M. Shiozaki et al., J. Org. Chem. 39, 2399 (1983); M. Shiozaki et al., Tetrahedron 40, 1795 (1984) and Tetrahedron Lett. 1984, 2793; A. G. M. Barrett, J. Org. Chem. 49, 1679 (1984)).

It is also known that direct reaction of 4-acetoxyazetidinones with lithium enolates provides poor yields and can likewise only be carried out with esters which are insensitive to organometallic compounds (compare T. Kametani et al., Heterocycles 14, 1967 (1980); T. Kametani et al., J. Chem. Soc., Perkin I 1981, 2228).

It has now been found that 4-[3-carboxy-3-diazo-2-oxopropyl]azetidin-2-ones of the general formula I ##STR4## in which R¹ represents hydrogen or represents an amino protective group,

R² represents hydrogen, represents optionally substituted alkyl, represents optionally substituted aryl, represents optionally substituted heterocyclyl, represents cyano, azido or halogen, or represents NHR¹, R¹ having the abovementioned meaning,

R³ represents hydrogen, represents optionally substituted alkyl, represents optionally substituted aryl, represents optionally substituted heterocyclyl, represents halogen, cyano, cyanato, azido, nitro or ═N--phenyl,

represents --COR⁵, --CO₂ R⁵, --CO--NR⁵ R⁶, --C(═NR⁵)NR⁵ R⁶, --CSNR⁵ R⁶

represents --NR⁵ R⁶, --NR⁵ --COR⁶, --NR⁵ --CO₂ R⁷, --NR°--CR⁵ (═NR⁶), --NR⁶ --CO--NR⁵ R⁶, --NR⁵ --CS--NR⁵ R⁶ --NR⁵ --C(═NR⁶)--NR⁵ R⁶, --NR⁵ --SO₂ R⁷,

represents --OR⁵, --OCOR⁵, --OCO--NR⁵ R⁶, --OSO₂ R⁷, --OSO₃ R⁵, --OPO(OR⁵)OR⁶, or

represents --SR⁵, --S(O)_(n) R⁷ n being 1 or 2, --SCOR⁵, --SO₂ OR⁵, --SO₂ NR⁵ R⁶, --SCN, --SCONHR⁵,

or represents --PX(OR⁵)OR⁶, --PX(NR⁵ R⁶)₂, --PX(OR⁵)NR⁵ R⁶

in which in each case

R⁵ and R⁶ are identical or different and represent hydrogen, represent optionally substituted alkyl, represent optionally substituted aryl, represent optionally substituted heterocyclyl, or optionally represent a protective group for hydroxyl, mercapto, amino or carboxyl,

R⁷ has the same meaning as R⁵ and R⁶ but does not represent hydrogen or a protective group, and X represents oxygen or sulphur, and

R⁴ represents a protective group for carboxyl or represents an ester radical which can be cleaved in vivo,

are obtained by reacting 4-acetoxy-2-azetidinones of the general formula II ##STR5## in which R¹ and R² have the abovementioned meaning,

with compounds of the general formula III ##STR6## in which R³ and R⁴ have the abovementioned meaning, in an inert solvent and in the presence of a base and a silylating agent, in a one-pot process.

It may be designated extremely surprising that the compound of the formula I is obtained in good yields by the process according to the invention. It was not to be expected from the state of the art that the compound of the general formula I can be prepared by the one-pot process, according to the invention, in homogeneous solution.

Apart from the simplicity of the procedure and the mild conditions, the process according to the invention has the advantage that there is no need for the separate, elaborate preparation of the precursors which are sensitive to hydrolysis. In addition, the new process also allows the use of the important nitrobenzyl protective groups. The silylating agent which is used simultaneously acts as a catalyst, which makes it unnecessary to use other Lewis acids. Furthermore, the process can also be used for the preparation of those compounds I in which the radical R³ is a substituent bonded via a heteroatom (for example --OCH₃).

The azetidinones which can be prepared by the process according to the invention are generally defined by the formula (I). In this formula

R¹ preferably represents hydrogen or preferably represents an amino protective group,

R² preferably represents hydrogen, preferably represents fluorine, chlorine, bromine or azido, preferably represents phenyl, preferably represents NHR¹, R¹ having the abovementioned meaning, preferably represents a radical of the formula ##STR7## X denoting sulphur or oxygen, or preferably represents straight-chain, branched or cyclic, saturated or unsaturated, alkyl having up to 6 C atoms, which is optionally substituted by fluorine, chlorine or the group OR⁸,

R⁸ representing hydrogen, or

preferably representing trimethylsilyl, triethylsilyl, triisopropylsilyl, tert.-butyldimethylsilyl, triphenylsilyl or trimethylsilylethoxycarbonyl, preferably represents benzyl, benzyloxycarbonyl, 2- or 4-nitrobenzyl, 2- or 4-nitrobenzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, or preferably represents formyl, acetyl, trichloroacetyl, trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl, tetrahydropyranyl or benzoyl,

R³ preferably represents hydrogen, preferably represents phenyl which is optionally substituted by chlorine, nitro, methyl, methoxy, methylthio, trifluoromethyl or by (optionally protected) hydroxyl, preferably represents fluorine, chlorine, bromine, cyano, cyanato or azido, preferably represents thienyl, furyl, imidazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, piperazinyl or pyrimidyl, each of which is optionally substituted by methyl, amino (optionally protected), fluorine, chlorine, trifluoromethyl or hydroxyl, preferably represents S-heterocyclyl, heterocyclyl having the meaning of triazolyl, tetrazolyl, thiadiazolyl, furyl, thienyl, pyridyl or pyrimidyl each of which is optionally substituted by methyl, amino, hydroxyl or acetylamino, preferably represents --COR⁵, --CO₂ R⁵, --CONHR⁵, amidino, preferably represents --NR⁵ R⁶, ureido, guanidino, preferably represents --OR⁵, --OCOR⁵, --OSO₂ R⁷, --OPO(OR⁵)₂, preferably represents --SR⁵, --S(O)_(n) R⁷ with n=1 or 2, --SCOR⁵, --SCONHR⁵, --SO₂ OR⁵, --SO₂ NHR⁵, --SCN or preferably represents --PO(OR⁵)₂, --PO(NR⁵ R⁶)₂ ,

where in each case

R⁵ and R⁶ are identical or different and represent hydrogen, represent straight-chain, branched or cyclic, saturated or unsaturated, alkyl having up to 6 C atoms, which is optionally substituted by phenyl or one or more fluorine, represents phenyl which is optionally substituted by nitro or methoxy, represents furyl, thienyl or pyridyl, or represents a protective group for hydroxyl, mercapto, amino or carboxyl, and

R⁷ has the same meaning as R⁵ and R⁶, but does not represent hydrogen or a protective group, or preferably represents straight-chain, branched or cyclic, saturated or unsaturated, alkyl having up to 6 C atoms, which is optionally substituted by phenyl, fluorine, chlorine, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl or a radical of the formula ##STR8## or by --CO₂ R⁵, --CONHR⁵, cyano, amidino, --NHR⁵, --NHCOCH₃, guanidino, azido, --OR⁵, --OCOR⁵, --OSO₂ R⁷, --OPO(OR⁵)₂, --SR⁵, --SO₂ R⁷, --SCOR⁵, --SO₂ NHR⁵, --PO(OR⁵)₂, --PO(NR⁵ R⁶)₂, where R⁵, R⁶ and R⁷ have the abovementioned meaning, and R⁴ preferably represents a carboxyl protective group or an ester radical which can be cleaved in vivo.

The one-pot process according to the invention for the preparation of compounds of the general formula I comprises several individual reaction steps.

If the starting material used is:

(a) (3R,4R)-4-Acetoxy-3-[1(R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one (R¹ in II=H) and allyl 2-diazo-3-oxo-pentanoate or

(b) (3R,4R)-4-acetoxy-3-[1(R)-1-tert.-butyldimethylsilyloxyethyl]-1-(4-methoxyphenyl)azetidin-2-one (R¹ in II=H) and 4-nitrobenzyl 2-diazo-3-oxobutanoate,

then the course of the reaction can be illustrated by the diagrams which follow: ##STR9##

In the compounds of the general formula I, II or III, where R², R³, R⁵, R⁶ and R⁷ denote optionally substituted alkyl they represent straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 10 C atoms, preferably up to 6 C atoms. Suitable substituents in this context are:

(a) phenyl which in turn can be substituted several times, preferably up to twice, by methyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, cyano, or hydroxyl, mercapto or amino each of which is optionally protected, dimethylamino, caramoyl, amidino, sulpho, sulphamoyl or halogen, preferably fluorine, chlorine or bromine,

(b) saturated or unsaturated 5-6-membered, optionally fused together, heterocyclyl having 1-4 identical or different heteroatoms from the group comprising O, S or N, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl, quinazolyl, purinyl, pteridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or a radical of the formula ##STR10## it being possible for the heterocycles in turn to carry the same substituents as already indicated for phenyl,

(c) halogen, preferably fluorine, chlorine or bromine,

(d) --COR⁹, --CO₂ R⁹, --CO--NR⁹ R¹⁰, --C(═NR¹⁰)NR⁹ R¹⁰, --CN,

(e) --NR⁹ R¹⁰, --NR⁹ --COR¹⁰, --N(COR⁹) (COR¹⁰), --NR⁹ CO₂ R¹¹, --NR¹⁰ --CR⁹ (═NR¹⁰), --NR¹⁰ --CO--NR⁹ R¹⁰, --NR⁹ --C(═NR¹⁰)--NR⁹ R¹⁰, --NR⁹ --SO₂ R¹¹, --N₃,

(f) --OR⁹, --OCOR⁹, --OCO--NR⁹ R¹⁰, --OSO₂ R¹¹, --OSO₃ R⁹, --OPO(OR⁹)OR¹⁰,

(g) --SR⁹, --S(O)_(n) R¹¹, n being 1 or 2, --SCOR¹¹, --SO₂ OR⁹, --SO₂ NR⁹ R¹⁰, or

(h) --PX(OR⁹)OR¹⁰, --PX(NR⁹ R¹⁰)₂, --PX(OR⁹)NR⁹ R¹⁰, where in each case

R⁹ and R¹⁰ are identical or different and represent hydrogen, represent straight-chain, branched or cyclic, saturated or unsaturated alkyl up to C₁₀, preferably up to C₆, represent phenyl or benzyl, represent heterocyclyl or heterocyclylmethyl, heterocyclyl having the meaning indicated under (b), or optionally represent a protective group for hydroxyl, mercapto, amino or carboxyl,

R¹¹ has the same meaning as R⁹ and R¹⁰ but does not represent hydrogen or a protective group, and X represents oxygen or sulphur.

Where R², R³, R⁵, R⁶ and R⁷ denote optionally substituted aryl, they preferably represent phenyl which can be substituted preferably once or twice, and optionally three times, by C₁ -C₄ -alkyl (preferably methyl or ethyl), C₁ -C₄ -alkoxy (preferably methoxy), C₁ -C₄ -alkylthio (preferably methylthio), trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen (preferably fluorine, chlorine or bromine), cyano, nitro, azido, dimethylamino, amino, hydroxyl, mercapto (each of which is optionally protected), sulpho, sulphamoyl, acetoxy or carbamoyl.

Where R², R³, R⁵, R⁶ and R⁷ denote optionally substituted heterocyclyl, they preferably represent saturated or unsaturated, 5-6-membered, optionally fused together, heterocyclyl having 1-4 identical or different heteroatoms from the group comprising O, S and N, and particularly preferably represent thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl, pyrrolidinyl, piperidinyl, piperazinyl, benzothiazolyl, benzimidazolyl, purinyl, pteridinyl, morpholinyl, thiomorpholinyl or a radical of the formula ##STR11## the substituents of heterocyclyl being those already indicated for aryl, and X represents sulphur or oxygen.

In R², R³, R⁵, R⁶ and R⁷ halogen preferably represents fluorine, chlorine or bromine.

When R¹ is an amino protective group then it is preferably one which is customary in β-lactam chemistry. Examples which may be mentioned as particularly preferred are vinyl, allyl, tert.-butyloxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl or 4-nitrobenzyl, 2-nitorbenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, 4-methoxyphenyl, formyl, benzoyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, methyloxycarbonyl, allyloxycarbonyl, trimethylsilyl, triethylsilyl or triphenylsilyl, tert.-butyldimethylsilyl, 2,4-dimethoxybenzyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyl, 4-methoxymethyloxyphenyl, bis(4-methoxyphenyl)methyl, tert.-butoxycarbonylmethyl, allyloxycarbonylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl or tetrahydropyranyl.

The terms aminoprotective group and protective groups of hydroxyl and mercapto in the radicals R², R³ and R⁵ -R¹¹ also have the same meaning.

Where R⁴ and R⁵, R⁶, R⁹ and R¹⁰ denote a carboxyl protective group they represent the protective groups customary in β-lactam chemistry. Groups which are easily eliminated may be mentioned as preferred, such as methyl, ethyl, tert.-butyl, decyl, 2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl and triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxyphenyl, 4-nitrobenzyl, 2-nitrobenzyl, 2,4-dimethoxybenzyl, trimethylsilylethyl, dimethyl-tert.-butylsilylethyl, trimethylsilyl, dimethyl-tert.-butylsilyl, acetonyl, 1-phenoxyethyl or 2-methyl-2-propenyl.

The term carboxyl protective group in the radicals R², R³, R⁵, R⁶, R⁹ and R¹⁰ has the same meaning.

Where R⁴ represents an ester radical which can be easily cleaved in vivo, this means pharmaceutically tolerated ester radicals which are easily hydrolyzed in vivo to give free carboxyl groups (R⁴ ═H).

Ester radicals R⁴ of this type are well known in the area of penicillins. In most cases, they improve the absorption properties of the β-lactam compound. In addition, the nature of R⁴ should be such that it confers on a compound of the formula (I) pharmaceutically acceptable properties and, on cleavage in vivo, releases pharmaceutically acceptable fragments. Examples of groups R⁴ of this type can be found in German Offenlegungsschrift No. 2,517,316. Preferred ester groups R⁴ are those of following formulae ##STR12## in which R¹² and R¹³ are identical or different and represent hydrogen, represent phenyl, or represent C₁ -C₄ -alkyl, preferably methyl,

R¹⁴ and R¹⁵ are identical or different and represent hydrogen or represent C₁ -C₄ -alkyl, preferably methyl, and

R¹⁶ represents C₁ -C₆ -alkyl, preferably C₁ -C₄ -alkyl.

Some of the compounds of the general formula I are already known but have been prepared by different processes [compare European Patent Application No. 78,026; J. O. Buynak et al., J. Chem. Soc., Chem. Commun. 1984, 948; U.S. Pat. Nos. 4,444,685 and 4,400,323; D. H. Shih et al., Heterocycles 21, 29 (1984)].

New, and thus the invention likewise relates to them, are compounds of the formula I in which

R¹ represents hydrogen or represents an amino protective group,

R² represents hydrogen, represents halogen, represents azido or phenyl, represents NHR¹, R¹ having the abovementioned meaning, represents a radical of the formula ##STR13## X denoting sulphur or oxygen, or represents straight-chain, branched or cyclic, saturated or unsaturated alkyl (up to C₆), which is optionally substituted by fluorine, chlorine or the group O--R⁸,

R⁸ representing hydrogen, representing trimethylsilyl, triethylsilyl, triisopropylsilyl, tert.-butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, representing benzyl, benzyloxycarbonyl, 2- or 4-nitrobenzyl, 2- or 4-nitrobenzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, or representing formyl, acetyl, trichloroacetyl, trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl, tetrahydropyranyl or benzoyl,

R³ represents aryl (C₆ -C₁₀) which is optionally substituted by chlorine, nitro, methyl, methoxy, methylthio, trifluoromethyl or (optionally protected) hydroxyl, or represents halogen, cyano, azido, cyanato, trifluoromethyl or nitro, represents --COR¹⁸, --CONR¹⁸ R¹⁹, --CSNR¹⁸ R¹⁹, or represents allyloxycarbonyl or 4-nitrobenzyloxycarbonyl, represents --NR¹⁹ R¹⁸, ureido, guanidino, amidino, --NR¹⁸ SO₂ R²⁰, represents --OSO₂ R²⁰, --OSO₃ R¹⁸ or --OPO(OR¹⁹)OR¹⁸, represents --SR¹⁸, --S(O)_(n) R²⁰ with n=1 or 2, --SCOR¹⁸, --SCONHR¹⁸, --SO₂ OR¹⁸, --SO₂ NR¹⁹ R¹⁸, --SCN, or represents --S-heterocyclyl, heterocyclyl having the meaning of triazolyl, tetrazolyl or thiadiazolyl, each of which is optionally substituted by methyl, amino, hydroxyl or acetylamino, or of furyl, thienyl, pyridyl or pyrimidyl, represents --PO(OR¹⁹)OR¹⁸ or represents ##STR14## or benzyl, R¹⁸ and R¹⁹ being identical or different and representing hydrogen, representing straight-chain or branched alkyl (up to C₆), representing phenyl or benzyl (phenyl optionally substituted by nitro, methyl or methoxy), or representing a protective group for hydroxyl, mercapto or amino, and

R²⁰ having the same meaning as R¹⁸ and R¹⁹ but not representing hydrogen or a protective group, and

R⁴ represents hydrogen or represents methyl, ethyl, tert.-butyl, decyl, 2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl or triphenylmethyl, acetoxymethyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, tert.-butyldimethylsilyl, 1-phenoxyethyl or 2-methyl-2-propenyl, 4-nitrobenzyl, 2-nitrobenzyl, trimethylsilylethyl or dimethyl-tert.-butylsilylethyl or represents a radical of the formula ##STR15## --CH₂ --OCO--C(CH₃)₃, --CH(CH₃)OCOOC₂ H₅ or --CH₂ OCOCH₃.

Preferred new compounds of the formula I are those in which

R¹ represents hydrogen or an amino protective group,

R² represents hydrogen, chlorine, bromine, azido, represents NHR¹, R¹ having the abovementioned meaning, represents a radical of the formula ##STR16## or represents methyl, ethyl, i-propyl, tert.-butyl, or represents ##STR17## R¹⁷ representing hydrogen, representing 3,4-dimethoxyphenyl, representing trimethylsilyl, tert.-butyldimethylsilyl, representing benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert.-butoxycarbonyl, allyloxycarbonyl or representing formyl or acetyl,

R³ represents phenyl, 3,4-dimethoxyphenyl, represents chlorine, bromine, cyano, cyanato, azido or CF₃, or represents --COR¹⁸, --CONR¹⁹ R¹⁸, represents allyloxycarbonyl or 4-nitrobenzyloxycarbonyl, represents --NHR¹⁸, ureido, guanidino, amidino, --NHSO₂ R²⁰, represents --OSO₂ R²⁰, --OPO(OR¹⁹)OR¹⁸, represents --S--R¹⁸, --SCOR¹⁸, --SO₂ OR¹⁸, --SO₂ NHR¹⁸, --SCN, --SO₂ R²⁰, --SCONH₂ or represents -S-pyridyl, -S-pyrimidyl, -S-methyltetrazolyl, -S-thiadiazolyl, 2-aminothiadiazolyl or represents ##STR18## R¹⁸ and R¹⁹ being identical or different and representing hydrogen or representing straight-chain or branched alkyl (up to C₄), representing phenyl, 4-methylphenyl or benzyl, or representing a protective group for hydroxyl, mercapto or amino, and R²⁰ having the same meaning as R¹⁹ and R¹⁸ but not representing hydrogen or a protective group, and

R⁴ represents hydrogen or represents methyl, ethyl, tert.-butyl, 2,2,2-trichloroethyl, allyl, acetonyl, 4-nitrobenzyl, 2-nitrobenzyl, 4-methoxybenzyl, benzyl or trimethylsilylethyl, or represents a radical of the formula ##STR19##

The terms amino protective group or protective group for hydroxyl or mercapto have the meaning which has already been given above.

Apart from the products detailed in the examples, the following compounds of the general formula (I) are particularly preferred:

    __________________________________________________________________________     R.sup.1    R.sup.2 R.sup.3         R.sup.4                                     __________________________________________________________________________                 ##STR20##                                                                             PhSO.sub.2      CH.sub.2CHCH.sub.2                          H          "       CH.sub.3 SO.sub.2 O                                                                            "                                           H          "       CH.sub.3 SO.sub.2                                                                              "                                           H          "       CH.sub.3 S      "                                           H          "       H.sub.2 NSO.sub.2                                                                              "                                           H          "       H.sub.2 NCOS    "                                           H          "       (CH.sub.3).sub.2 N                                                                             "                                           H          "       H.sub.2 N       "                                           H          "       PhCH.sub.2 NH   "                                           H          "       CH.sub.3 CONH   "                                           H          "       CHNOH           "                                           H          "       CH.sub.3 SO.sub.2 NH                                                                           "                                           H          "                                                                                       ##STR21##      "                                           H          "                                                                                       ##STR22##      "                                           H          "       CHO             "                                           H                                                                                          ##STR23##                                                                             CF.sub.3        CH.sub.2CHCH.sub.2                          H          "                                                                                       ##STR24##      "                                           H                                                                                          ##STR25##                                                                             COOCH.sub.2CHCH.sub.2                                                                          "                                           H          "       Ph              "                                           H          "       Cl              "                                           H          "       N.sub.3         "                                           H          "       CH.sub.3 SO.sub.2                                                                              "                                           H          "       CF.sub.3        "                                           H                                                                                          ##STR26##                                                                             PhSO.sub.2                                                                                      ##STR27##                                  H          "       CH.sub.3 SO.sub.2                                                                              "                                           H          "       CH.sub.3 S      "                                           H          "       H.sub.2 NSO.sub.2                                                                              "                                           H          "       H.sub.2 NCOS    "                                           H          "       (CH.sub.3).sub. 2 N                                                                            "                                           H                                                                                          ##STR28##                                                                             H.sub.2 N                                                                                       ##STR29##                                  H          "       PhCH.sub.2 NH   "                                           H          "       CH.sub.3 CONH   "                                           H          "       CHONH           "                                           H          "       CH.sub.3 SO.sub.2 NH                                                                           "                                           H          "                                                                                       ##STR30##      "                                           H          "                                                                                       ##STR31##      "                                           H          "       CHO             "                                           H          "       CF.sub.3        "                                           H          "                                                                                       ##STR32##      "                                           H          "                                                                                       ##STR33##      "                                           H          "       CH.sub.3 SO.sub.2 O                                                                            "                                           H          "                                                                                       ##STR34##      "                                            ##STR35## "       Cl              CH.sub.2CHCH.sub.2                          "          "       N.sub.3         "                                            ##STR36##                                                                                 ##STR37##                                                                             CH.sub.3 SO.sub.2                                                                              CH.sub.2CHCH.sub.2                          "          "       CHONH           "                                           H                                                                                          ##STR38##                                                                             Cl              "                                           H          "       N.sub.3         "                                           H          "       CH.sub.3 SO.sub.2                                                                              "                                           H          "       PhSO.sub.2      "                                           H          "       CH.sub.3 S      "                                           H          "       H.sub.2 NSO.sub.2                                                                              "                                           H          "       H.sub.2 NCOS    "                                           H          "       NCS             "                                           H          "       (CH.sub.3).sub.2 N                                                                             "                                           H          "       H.sub.2 N       "                                           H          "       PhCH.sub.2 NH   "                                           H                                                                                          ##STR39##                                                                             CH.sub.3 CONH   CH.sub.2CHCH.sub.2                          H          "       CH.sub.3 SO.sub.2 NH                                                                           "                                           H          "                                                                                       ##STR40##      "                                           H          "                                                                                       ##STR41##      "                                           H          "       CHONH           "                                           H          "       CHO             "                                           H          "       CF.sub.3        "                                           H          "                                                                                       ##STR42##      "                                           H          "       Cl                                                                                              ##STR43##                                  H          "       N.sub.3         "                                           H          "       CH.sub.3 SO.sub.2                                                                              "                                           H          "       PhSO.sub.2      "                                           H          "       CH.sub.3 S      "                                           H                                                                                          ##STR44##                                                                             PhS                                                                                             ##STR45##                                  H          "       H.sub.2 NSO.sub.2                                                                              "                                           H          "       H.sub.2 NCOS    "                                           H          "       NCS             "                                           H          "       (CH.sub.3).sub.2 N                                                                             "                                           H          "       H.sub.2 N       "                                           H          "       PhCH.sub.2 NH   "                                           H          "       CH.sub.3 CONH   "                                           H          "       CHONH           "                                           H          "       CH.sub.3 SO.sub.2 NH                                                                           "                                           H          "                                                                                       ##STR46##      "                                           H          "                                                                                       ##STR47##      "                                           H          "                                                                                       ##STR48##      "                                           H                                                                                          ##STR49##                                                                             CHO                                                                                             ##STR50##                                  H          "       CF.sub.3        "                                           H          "                                                                                       ##STR51##      "                                           H                                                                                          ##STR52##                                                                             Cl              "                                           H          "       CH.sub.3 SO.sub.2                                                                              "                                           H          "       PhSO.sub.2      "                                           H          "       CH.sub.3 S      "                                           __________________________________________________________________________

The compounds of the general formula II are known or can be prepared by methods known from the literature [compare German Offenlegungsschrift No. 19 06 401; A. Oida et al., Chem. Pharm. Bull. 29, 2899 (1981), M. Shiozaki et al., Tetrahedron 39, 2399 (1983); M. Shiozaki et al., Tetrahedron 40, 1795 (1984), W. J. Leanza et al., Tetrahedron 39, 2505 (1983), T. Kametani et al., J. Chem. Soc. Perkin I 1981, 2228; J. L. Roberts et al., Synthetic Communications 13, 797 (1983)].

The compounds of the general formula III are known or can be prepared by methods known from the literature [compare S. Julia et al., Compt. Rend. Acad. Sci., Paris, Section C 246, 1890 (1967), European Patent Application No. 78 026, European Pat. No. 52 299, R. M. Kellogg et al., J. C. S. Chem. Comm. (1977) 932].

All inert solvents are suitable as diluents. These preferably include ethers, such as dimethoxyethane, diglyme, triglyme, tetrahydrofuran, dioxane, diethyl ether or tert.-butyl methyl ether, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, 1,1,2-trichloroethane, dichloroethane or trichloroethylene, chlorobenzene, dichlorobenzene, ethyl acetate, toluene or cyclohexane.

The reaction is generally carried out at temperatures from -30° C. to +50° C., preferably at room temperature. All tertiary amines are suitable as the bases. Those which may be mentioned as preferred are triethylamine, tripropylamine or tributylamine, ethyl diisopropylamine, pyridine, picoline, lutidine, N-methylmorpholine, N-methylpiperidine, 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-3-ene (DBN).

All silylating agents which can also act as Lewis acids are suitable as silylating agents and catalysts. These include, preferably, trialkylsilyl perfluoroalkanesulphonates, trialkylsilyl alkanesulphonates, trialkylsilyl arylsulphonates, trialkylsilyl perfluoroalkanoates, trialkylsilyl alkanoates, trialkylsilyl halides, trialkylsilyl perchlorates, trialkylsilyl difluorophosphates, trialkylsilyl dichlorophosphates, trialkylsilyl fluorosulphonates, N,O-bis(trialkylsilyl)acetamides and trialkylsilyl cyanides. Particularly suitable are trimethylsilyl trifluoromethanesulphonate, trimethylsilyl nonafluorobutanesulphonate, trimethylsilyl trifluoroacetate, trimethylsilyl perchlorate, trimethylsilyl bromide, trimethylsilyl difluorophosphate, trimethylsilyl fluorosulphonate and N,O-bis(trimethylsilyl)trifluoroacetamide.

To carry out the process, it is necessary to introduce first

(a) 0.1-1, preferably 0.5-1, equivalent of the compound II per equivalent of the compound III,

(b) 1-2, preferably 1-1.5, equivalents of silylating agent per equivalent of the compound III, and

(c) 1.01-3, preferably 1.05-2, equivalents of base (amine) per equivalent of silylating agent,

and after 0.1-24 h, preferably 0.1-12 h, to add sufficient additional silylating agent that the silylating agent is then present in a slight excess, preferably in a catalytic excess, over the base (amine).

When carrying out the process, in addition to the abovementioned ratios of amounts of silylating agent and base (amine), one additional equivalent of silylating agent and of base (amine) is to be used for each hydroxyl, mercapto and amino group which is free, that is to say which is to be protected, in the compounds II and III (for example when R¹ =H).

The reaction rate substantially depends on the amount of catalyst used, that is to say the excess of silylating agent. The reaction takes place within 0.1 to 48 h, preferably from 0.1 to 24 h.

The compounds of the general formula I are valuable intermediates for the synthesis of effective antibiotics [compare, inter alia, D. H. Shih et al., Heterocycles 21, 29 (1984)].

The examples which follow serve to describe the invention further but without restricting it.

(A) Examples for the preparation of compounds of the formula III:

PREPARATION EXAMPLE 1 ##STR53## Allyl 2-diazo-3-oxobutanoate

55.4 ml (0.4 mole - 2 equivalents) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 28.43 g (0.2 mole) of allyl acetoacetate and 43.39 g (0.22 mole - 1.1 equivalents) of p-toluenesulphonyl azide in 400 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 3.5 h, then 50 g of kieselguhr were added, evaporation in vacuo was carried out and then chromatography on 400 g of silica gel (toluene:ethyl acetate 96:4). 31.9 g (95%) of the title compound were obtained as a pale yellow oil, Rf: 0.36 (toluene:ethyl acetate 9:1).

IR (CHCl₃) 2141 (N₂), 1714 (C═O), 1651 cm⁻¹ (C═O).

¹ H-NMR (200 MHz, CDCl₃) δ 2.50 (s, 3H, CH₃), 4.76 (m, 2H, --CH₂ --CH═CH₂), 5.3-5.4 (m, 2H, --CH₂ --CH═CH₂), 5.9-6.1 (m, 1H, --CH₂ --CH--═CH₂).

C₇ H₈ N₂ O₃ : (168.2) calculated: C 50.00, H 4.80, N 16.66. found: C 49.9, H 4.8, N 16.6.

PREPARATION EXAMPLE 2 ##STR54## Allyl 2-diazo-3-oxopentanoate

a. In analogy to the method described by L. Weiler et al., J. Am. Chem. Soc. 96, 1082 (1974), 8.3 g (27%) of allyl 3-oxopentanoate were obtained as a colorless liquid, boiling point 84° C./14 mm Hg, Rf: 0.34 (toluene:ethyl acetate 9:1), from 28.43 g (0.2 mole) of allyl 3-oxobutanoate and 15 ml (0.24 mole - 1.2 equivalents) of methyl iodide and chromatography of the crude product on 700 g of silica gel (toluene:ethyl acetate 95:5) followed by distillation.

IR (CHCl₃) 1741 (C═O), 1714 cm⁻¹ (C═O).

¹ H-NMR (300 MHz, CDCl₃) δ 1.10 (t, J=8 Hz, 3H, CH₂ CH₃), 2.60 (q, J=8 Hz, 2H, CH₂ CH₃), 3.48 (s, 2H, CH₂), 4.65 (m, 2H, CH₂ --CH═CH₂), 5.2-5.4 (m, 2H, CH═CH₂), 5.8-6.0 (m, 1H, CH₂ --CH═CH₂).

C₈ H₁₂ O₃ : (156.2) calculated: C 61.52, H 7.74. found: C 61.4, H 7.8.

b. As described for preparation Example 1, 9.34 g (97%) of the title compound were obtained as a pale yellow oil, Rf: 0.5 (toluene:ethyl acetate 9:1), from 8.3 g (53.1 mmol) of allyl 3-oxopentanoate and chromatography of the crude product on 130 g of silica gel (toluene:ethyl acetate 96:4).

IR (CHCl₃) 2137 (N₂), 1712 (C═O), 1650 cm⁻¹ (C═O).

¹ H-NMR (200 MHz, CDCl₃) δ 1.16 (t, J=8 Hz, 3H, CH₃), 2.89 (q, J=8 Hz, 2H, CH₂ CH₃), 5.52 (m, 2H, CH₂ --CH═CH), 5.3-5.4 (m, 2H, CH═CH₂), 5.9-6.1 (m, 1H, CH₂ --CH═CH₂).

C₈ H₁₀ N₂ O₃ : (182.2) calculated: C 52.74, H 5.53, N 15.38. found: C 52.1, H 5.5, N 14.8.

PREPARATION EXAMPLE 3 ##STR55## 4-Nitrobenzyl 2-diazo-3-oxobutanoate

35.0 ml (0.25 mole - 1.8 equivalent) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 33.18 g (0.14 mole) of 4-nitrobenzyl acetoacetate and 30.40 g (0.15 mole) of p-toluenesulphonyl azide in 280 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 2 h, and then the resulting precipitate was filtered off with suction, washed with ether and dried over P₄ O₁₀ under high vacuum. 20.3 g (55%) of the title compound were obtained as colorless crystals, melting point 132° C. A further 6.3 g (17%) of the title compound were obtained by chromatography of the filtrate solution on 400 g of silica gel (toluene:ethyl acetate 9:1), Rf: 0.35 (toluene:ethyl acetate 9:1).

IR (KBr) 2144 (N₂), 1709 (C═O), 1662 (C═O), 1514 (NO₂ asym.), 1343 cm⁻¹ (NO₂ sym.).

¹ H-NMR (200 MHz, DMSO) δ 2.44 (s, 3H, CH₃), 5.44 (s, 2H, CH₂), 7.72 (d, J=9 Hz, 2H, H_(arom).), 8.28 (d, J=9 Hz, 2H, H_(arom).).

C₁₁ H₉ N₃ O₅ : (263.2) calculated: C 50.20, H 3.45, N 15.96. found: C 50.2, H 3.4, N 15.9.

PREPARATION EXAMPLE 4 ##STR56## Methyl 2-diazo-4-methoxy-3-oxobutanoate

As described for preparation Example 1, 3.05 g (89%) of the title compound were obtained as a pale yellow oil, Rf: 0.35 (toluene:ethyl acetate 3:1), from 2.92 g (20 mmol) of methyl 4-methoxyacetoacetate and chromatography of the crude product on 900 g of silica gel (toluene:ethyl acetate 3:1).

IR (CHCl₃) 2138 (N₂), 1711 (C═O), 1665 cm⁻¹ (C═O).

¹ H-NMR (250 MHz, CDCl₃) δ 3.48 (s, 3H, COOCH₃), 3.86 (s, 3H, OCH₃), 4.53 (s, 2H, CH₂).

C₆ H₈ N₂ O₄ : (172.1) calculated: C 41.86, H 4.68, N 16.27. found: C 42.1, H 4.7, N 16.6.

PREPARATION EXAMPLE 5 ##STR57## tert.-Butyl 4-benzyloxy-2-diazo-3-oxobutanoate

5.54 ml (40 mmol - 2 equivalents) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 5.29 g (20 mmol) of tert.-butyl 4-benzyloxyacetoacetate and 4.34 g (22 mmol) of p-toluenesulphonyl azide in 40 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 30 min, 8 g of kieselguhr were added, and evaporation in vacuo and chromatography on 100 g of silica gel (toluene:ethyl acetate 95:5) were carried out. 3.98 g (69%) of the title compound were obtained as colorless crystals, melting point: 68° C., Rf: 0.31 (toluene:ethyl acetate 95:5).

IR (KBr) 2144 (N₂), 1700, 1673 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ 1.51 (s, 9H, C(CH₃)₃), 4.59 (s, 2H, CH₂), 4.67 (s, 2H, CH₂), 7.3-7.5 (m, 5H, Ph).

C₁₅ H₁₈ N₂ O₄ : (290.3) calculated: C 62.06, H 6.23, N 9.65. found: C 62.1, H 6.2, N 9.6.

PREPARATION EXAMPLE 6 ##STR58## tert.-Butyl 4-acetylthioacetoacetate

2.40 g (21.0 mmol) of dry potassium thioacetate were added to a solution, which had been cooled to 0° C., of 3.85 g (20.0 mmol) of tert.-butyl 4-chloroacetoacetate in 40 ml of anhydrous acetonitrile, and the mixture was stirred at this temperature for 30 min. It was then poured into a mixture of NaCl solution and ethyl acetate, the organic phase was separated off, extraction with 2×30 ml of ethyl acetate was carried out, and the extract was washed with water and dried over MgSO₄. After evaporation of the solvent in vacuo and chromatography of the residue on 60 g of silica gel (toluene:ethyl acetate 95:5), 3.87 g (83%) of the title compound were obtained as a colorless oil, Rf: 0.24 (toluene:ethyl acetate 95:5).

IR (CHCl₃) 1740-1710 cm⁻¹ (C═O).

¹ H-NMR (250 MHz, CDCl₃) δ 1.50 (s, 9H, C(CH₃)₃), 2.42 (s, 3H, CH₃ CO), 3.53 (s, 2H, CH₂), 3.90 (s, 2H, CH₂).

PREPARATION EXAMPLE 7 ##STR59## tert.-Butyl 4-benzylthioacetoacetate

7.04 ml (60 mmol) of benzylmercaptan were slowly added dropwise to a suspension of 1.8 g (60 mmol) of sodium hydride (80% in liquid paraffin) in 50 ml of anhydrous THF at room temperature. The mixture was then stirred for 15 min and subsequently cooled to 0° C. At this temperature, a solution of 10.57 g (55 mmol) of tert.-butyl 4-chloroacetoacetate in 23 ml of THF was added within 1 h. The icebath was removed, and the mixture was stirred for a further 1 h at room temperature and then neutralized by addition of a few drops of 10% strength HCl. The solvent was evaporated in vacuo, ether was added several times, and the extracts were washed with water and dried over MgSO₄. Evaporation of the ether in vacuo produced an oil which was purified by chromatography on 800 g of silica gel (toluene). 12.74 g (83%) of the title compound were obtained in the form of a colorless oil, Rf: 0.13 (toluene).

IR (CHCl₃) 1740-1710 cm⁻¹ (C═O, β-keto ester).

¹ H-NMR (200 MHz, CDCl₃) δ 1.49 (s, 9H, C(CH₃)₃), 3.22 (s, 2H, CH₂), 3.52 (s, 2H, CH₂), 3.68 (s, 2H, CH₂), 7.33 (s, 5H, Ph).

C₁₅ H₂₀ O₃ S: (280.4) calculated: C 64.3, H 7.2, S 11.4. found: C 64.3, H 7.2, S 11.3.

PREPARATION EXAMPLE 8 ##STR60## tert.-Butyl 4-chloro-2-diazo-3-oxobutanoate

As described for Preparation Example 1, 2.67 g (84%) of the title compound were obtained as crystals, Rf: 0.29 (toluene), melting point: 40°-41° C., from 2.79 g (14.5 mmol) of tert.-butyl 4-chloroacetoacetate and filtration of the crude product on 30 g of silica gel (toluene).

IR (CHCl₃): 2140 (N₂), 1708 (C═O), 1662 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ 1.54 (s, 9H, C(CH₃)₃), 4.60 (s, 2H, CH₂).

C₈ H₁₁ N₂ O₃ Cl: (218.6) calculated: C 43.9, H 5.1, N 12.8. found: C 44.0, H 5.1, N 13.3.

PREPARATION EXAMPLE 9 ##STR61## tert.-Butyl 4-acetylthio-2-diazo-3-oxobutanoate

As described for Preparation Example 1, 3.48 g (45%) of the title compound were obtained as an oil, Rf: 0.34 (toluene:ethyl acetate 95:5), from 6.97 g (30.0 mmol) of tert.-butyl 4-acetylthioacetoacetate after chromatography of the crude product on 280 g of silica gel.

IR (CHCl₃) 2140 (N₂), 1705 (C═O) 1656 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃), 1.55 (s, 9H, C(CH₃)₃), 2.39 (s, 3H, COCH₃), 4.23 (s, 2H, CH₂).

C₁₀ H₁₄ N₂ O₄ S: (258.3) calculated: C 46.5, H 5.5, N 10.8. found: C 46.5, H 5.4, N 11.3.

PREPARATION EXAMPLE 10 ##STR62## tert.-Butyl 4-benzylthio-2-diazo-3-oxobutanoate

As described for Preparation Example 1, 3.4 g (74%) of the title compound were obtained as a yellow oil, Rf: 0.28 (toluene), from 4.21 g (15.0 mmol) of tert.-butyl 4-benzylthioacetoacetate after chromatography of the crude product on 100 g of silica gel (toluene).

IR (CHCl₃) 2145 (N₂), 1705, 1635 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ 1.52 (s, 9H, C(CH₃)₃), 3.58 (s, 2H, CH₂), 3.77 (s, 2H, CH₂), 7.3-7.4 (m, 5H, Ph).

C₁₅ H₁₈ N₂ O₃ S: (306.38) calculated: C 58.80, H 5.92, S 10.46. found: C 59.2, H 6.0, S 10.5.

PREPARATION EXAMPLE 11 ##STR63## Allyl 3-oxo-5-phthalimidopentanoate

A solution of 2.89 g (10.0 mmol) of ethyl 3-oxo-5-phthalimidopentanoate in 14 ml of allyl alcohol was heated at 80° C. in the presence of catalytic amounts of p-toluenesulphonic acid hydrate for 3 days. The solvent was then evaporated in vacuo and the residue was purified by chromatography on 170 g of silica gel (toluene:ethyl acetate 4:1). The title compound was obtained as colorless crystals, melting point: 53°-55° C., Rf: 0.40 (toluene:ethyl acetate 4:1).

IR (CHCl₃) 1716 cm⁻¹ (C═O).

¹ H-NMR (300 MHz, CDCl₃) 3.01 (t, J=7 Hz, 2H, CH₂ CO), 3.54 (s, 2H, COCH₂ CO), 4.0 (t, J=7 Hz, 2H, CH₂ N), 4.65 (m, 2H, CH₂ --CH═CH₂), 5.2-5.4 (m, 2H, CH═CH₂), 5.8-6.0 (m, 1H, CH₂ --CH═CH₂), 7.73, 7.87 (m, each 2H, H_(arom).).

C₁₆ H₁₅ NO₅ : (301.3) calculated: C 63.78, H 5.02, N 4.64. found: C 63.8, H 5.4, N 4.3.

PREPARATION EXAMPLE 12 ##STR64## Allyl 4-(diethylphosphinyl)-3-oxobutanoate

A solution of allyl 4-bromo-3-oxobutanoate (German Offenlegungsschrift No. 2,048,470) in 10 ml of THF was slowly added dropwise to a suspension, which had been cooled to -30° C., of 300 mg (10.0 mmol) of sodium hydride in THF. The mixture was stirred at -30° C. for 15 min and then 0.65 ml (5.02 mmol) of diethyl phosphite was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. To work up, the mixture was poured into a mixture of ethyl acetate and saturated NaHCO₃ solution, extraction with ethyl acetate was carried out, followed by washing with saturated NaCl solution and drying over MgSO₄.

After evaporation of the solvent in vacuo and chromatography of the residue on 90 g of silica gel (toluene:ethyl acetate 1:4), 705 mg (51%) of the title compound were obtained as an oil, Rf: 0.30 (toluene:ethyl acetate 1:4).

IR (CHCl₃) 1735, 1718, 1640, 1250 cm⁻¹ (P═O).

¹ H-NMR (300 MHz, CDCl₃) δ 1.35 (t, J=7.5 Hz, 6H, CH₃ CH₂), 3.26 (d, J=23 Hz, 2H, PCH₂ CO), 3.71 (s, 2H, COCH₂ CO), 4.17 (q, J=7.5 Hz, 4H, CH₃ CH₂), 4.66 (m, CH₂ --CH═CH₂), 5.2-5.4 (m, 2H, CH═CH₂), 5.8-6.0 (m, 1H, CH₂ --CH═CH₂).

PREPARATION EXAMPLE 13 ##STR65## Allyl 2-diazo-3-oxo-4-phenylsulphonylbutanoate

2.59 g (15.0 mmol) of m-chloroperbenzoic acid were added to a solution, which had been cooled to 0° C., of 1.38 g (5.0 mmol) of allyl 2-diazo-3-oxo-4-phenylthiobutanoate in 10 ml of dichloromethane, and the mixture was stirred at this temperature for 1 h. To work up, it was poured into saturated NaHCO₃ solution, and extraction with ethyl acetate was carried out, followed by washing with water and drying over MgSO₄. After evaporation of the solvent in vacuo and filtration of the crude product on 30 g of silica gel (toluene:ethyl acetate 9:1), 883 mg (57%) of the title compound were obtained, Rf: 0.24 (toluene:ethyl acetate 95:5).

IR (CHCl₃) 2150 (N₂), 1716, 1647, 1328 (SO₂ as.), 1160 cm⁻¹ (SO₂ sym.).

¹ H-NMR (200 MHz, CDCl₃) δ 4.78 (d, J=7 Hz, 2H, CH₂ --CH═CH₂), 4.88 (s, 2H, SO₂ CH₂ CO), 5.4-5.5 (m, 2H, CH═CH₂), 5.9-6.1 (m, 1H, CH₂ --CH═CH₂), 7.55-7.75 (m, 3H, Ph), 8.02 (m, 2H, Ph).

C₁₃ H₁₂ N₂ O₅ S (308.3): calculated: C 50.64, H 3.92, N 9.09, S 10.40. found: C 50.3, H 3.9, N 8.9, S 10.4.

PREPARATION EXAMPLE 14 ##STR66## 4-Nitrobenzyl 3-oxopentanoate

A suspension of 55.3 g (0.36 mole) of 4-nitrobenzyl alcohol and 56.2 g (0.39 mole) of ethyl 3-oxopentanoate in 360 ml of toluene was heated to boiling. About 300 ml of toluene were distilled out over the course of 10 h, then the mixture was cooled and another 200 ml were added and this procedure was repeated. After cooling, the mixture was filtered through kieselguhr, which was washed with toluene, and the filtrate solution was evaporated in vacuo. 89 g (98%) of the title compound were obtained as an oil, Rf: 0.42 (toluene:ethyl acetate 4:1).

IR (CHCl₃), 1751 (C═O), 1722 (C═O), 1524 (NO₂ asym.), 1351 cm⁻¹ (NO₂ sym.).

¹ H-NMR (300 MHz, CDCl₃) δ 1.10 (t, J=7.5 Hz, 3H, CH₃ CH₂), 2.59 (q, J=7.5 Hz, 2H, CH₃ CH₂), 3.57 (s, 2H, COCH₂ CO), 5.29 (s, 2H, CO₂ CH₂), 7.53 (d, J=9 Hz, 2H, H_(arom).), 8.20 (d, J=9 Hz, 2H, H_(arom).).

In analogy to the preparation examples already described, the following 4-substituted acetoacetic esters were also obtained (Preparation Examples 15-21, Table 1): ##STR67## From these were obtained, as described for Preparation Example 1, the corresponding diazo compounds by diazo transfer (Preparation Examples 22-34, Table 2): ##STR68##

    TABLE 1       Prep.         Ex.   prepared by Yield Rf IR 1-HNMR No. R.sup.3 R.sup.4      Prep. Ex. % (Tol.: Ethylac.) (cm.sup.-1) (200 MHz, CDCl.sub.3) δ      ppm Analysis        15 CH.sub.2 COS CH.sub.2CHCH.sub.2 6 73 0.24 (95:5) 1724 2.36 (s, 3H,      CH.sub.2 CO),  C.sub.9 H.sub.12 O.sub.4 S (216.3)       1697 3.60 (s,      2H, COCH.sub.2       CO), calc: C 49.99 N 5.59        S 14.82       ##STR69##       fd: C 50.0 N 5.6       ##STR70##        S 14.7       ##STR71##       16      ##STR72##       CH.sub.2CHCH.sub.2 11 40 0.36 (95:5) 17441721       ##STR73##       calc:fd: C.sub.13 H.sub.14 O.sub.3 (218.2)C 71.54 N 6.47C 71.5 N 6.7      17       ##STR74##       CH.sub.2CHCH.sub.2 6 86 0.27 (7:3) 1738 (sh)17191650       ##STR75##       calc:fd: C.sub.9 H.sub.12 N.sub.4 O.sub.3 S (256.3)C 42.18 N 4.72N      21.86 S 12.51C 42.0 H 4.7N 21.5 N 12.5  18 N.sub.2 CH.sub.2CHCH.sub.2      12, but. 43 0.34 (95:5) 2110 (N.sub.3) 3.58 (s, 2H, COCH.sub.2 CO),      C.sub.7 H.sub.9 N.sub.3 O.sub.3 (183.2)    only 1   1740 (sh) 4.15 (s,      2H, N.sub.3 CH.sub.2 CO), calc: C 45.90 N 4.95    equivalent   1725       ##STR76##       fd: C 45.8 N 4.9    of NaH       ##STR77##       ##STR78##        19 COOCH.sub.2CHCH.sub.2 CH.sub.2CHCH.sub.2 11 28 0.29 (96:4) 1735      3.66 (s, 4H, COCH.sub.2 CO),  C.sub.11 H.sub.14 O.sub.3 (226.2)      1720       ##STR79##       calc: C 58.40 N 6.24       1655       ##STR80##       fd: C 58.4 N 6.3       ##STR81##            +  COOCH.sub.2 CH.sub.2CHCH.sub.2 from 16 0.21 (96:4) 1740 3.64      (s, 2H, CH.sub.2),  C.sub.9 H.sub.11 O.sub.3    dimethyl   1720 3.66 (s,      2H, CH.sub.2), calc: C 54.27 N 5.57    ester   1650 3.77 (s, 3H,      COOCH.sub.2), fd: C 54.0 N 6.0       ##STR82##       ##STR83##       ##STR84##                20      ##STR85##       ##STR86##       14 98 0.31 (95:5) -- 3.54 (s, 2H, COCH.sub.2 CO), 3.86(s, 2H, CH.sub.2      Ph), 5.27 (s, 2H,COOCH.sub.2), 7.51 (d, J=9 Hz, 2H,Harom.), 8.20 (d, J=9      Hz, 2H,Harom.). --       21      ##STR87##       ##STR88##       14 97 0.40 (7:3) -- 3.55 (s, 2H, CH.sub.2), 3.76 (s, 2H,CH.sub.2), 3.85      (s, 3H, OCH.sub.3),3.86 (s, 3H, OCH.sub.2), 5.23 (s, -MX,1 2H, CO.sub.2      CH.sub.2), 6.7-6.9 (m, 3H,Harom.), 7.50 (d, J=9 Hz, 2H,2H, Harom.), 8.22      (d, J=9 Hz,2H, Harom.). --  21 (a) CF.sub.3 CH.sub.2CHCH.sub.2 acc. toK.      P. ZeilerSynthesis(1985) 334. 22 0.42 (9:1) 17181650       ##STR89##       bp.: 140-150°       C./10 mm(Kugelrohr)

    TABLE 2       Prep.        Ex.   Yield Rf IR .sup.1 HNMR No. R.sup.3 R.sup.4 %      (Tol.:Ethylac. (cm.sup.-1) (200 MHz,CDCl.sub.3)δppm Analysis        22 Cl CH.sub.3CHCH.sub.3 76 0.24 (1:0) 2147 (N.sub.3) 4.64 (s, 2H,      CH.sub.3 Cl), C.sub.2 H.sub.3 ClN.sub.3 O.sub.3 (202.6)      1714       ##STR90##       calc:C 41.50 N 3.48      1666       ##STR91##       N 13.8       ##STR92##       fd:C 41.7 H 3.6        N 13.8 23 CH.sub.3 COS CH.sub.3CHCH.sub.3 89      0.31 (95:5) 2144 (N.sub.3) 2.39 (s, 3H, CH.sub.3 CO), C.sub.9 H.sub.10      N.sub.3 O.sub. 4       S (242.3)      1715      ##STR93##       calc:C 44.62 N 4.16      1658       ##STR94##       N 11.56 S 13.23      1327       ##STR95##       fd:C 45.0 N 4.2       ##STR96##       N 11.5 N 13.6       24      ##STR97##       CH.sub.3CHCH.sub.3 88 0.21 (1:0) 2143 (N.sub.3)17151649       ##STR98##       C.sub.13 H.sub.12 N.sub.3       O.sub.3 (244.3) calc:C 63.93 N 4.95N 11.47fd:C 63.8 N 5.0N 11.7  25       ##STR99##       CH.sub.3CHCH.sub.3 80 0.34 (9:1) 2143 (N.sub.3)17181650       ##STR100##       C.sub.16 N.sub.13 N.sub.3 O.sub.3 (327.3)calc:C 58.72 N 4.00N 12.84fd:C      58.7 N 4.0N 12.8       26      ##STR101##        CH.sub.2CHCH.sub.3 97 0.23 (4:1) 2134 (N.sub.3)17121655       ##STR102##       C.sub.9 H.sub.10 N.sub.6 O.sub.3 S (282.3)calc:C 38.30 N 3.57N 29.77 S      11.36fd:C 38.6 N 3.7N 29.5 S 11.2  27 N.sub.3 CH.sub.3CHCH.sub.3 34 0.39      (95:5) 2135 (N.sub.3) 4.40 (s, 2H, H.sub.3 CH.sub.3 CO),    68.4.sup.(a)       2110 (N.sub.3)       ##STR103##            1710       ##STR104##            1660       ##STR105##       28 NCS CH.sub.3CHCH.sub.3 76.sup.(b) 0.29 (95:5) 2146 (N.sub.3 4.33 (s,      2H, NCSCH.sub.3 CO), C.sub.6 N.sub.3 H.sub.3 O.sub.3 S (225.2)      SCN)       ##STR106##       calc:C 42.66 N 3.13      1713       ##STR107##       N 18.66 S 14.23      1655       ##STR108##       fd:C 42.9 N 3.1        N 18.7 S 14.1 29 CH.sub.3CHCH.sub.3OOC CH.sub.3CHC      H.sub.3 30 0.31 (95:5) 2147 (N.sub.3) 3.90 (s, 2H, COCH.sub.3 CO),      C.sub.11 N.sub.13 H.sub.3       O.sub.3 (252.2)      1718      ##STR109##       calc:C 52.38 N 4.80      1655       ##STR110##       N 11.11       ##STR111##       fd:C 52.4 N 4.9       ##STR112##       N 11.0       30      ##STR113##       CH.sub.3CHCH.sub.3 67 0.35 (0:1) 2150 (N.sub.3)171516451255 (P=0)       ##STR114##       C.sub.11 H.sub.12 N.sub.3 O.sub.6 P calc:C 43.43 N 5.63N 9.21 P         C      10.18fd: 43.6 N 5.6N 9.4 P 9.7  31 PhS CH.sub.3CHCH.sub.3 90.sup.(c)      0.55 (95:5) 2150 (N.sub.3) 4.18 (s, 2H, SCH.sub.3 CO),      1715       ##STR115##            1650       ##STR116##       ##STR117##             7.3-7.6 (m, 5H, Ph).       32 CH.sub.3      ##STR118##       71 0.56 (4:1) 2145 (N.sub.3)171316591519 (NO.sub.3 as.1352 (NO.sub.3      s.)       ##STR119##       C.sub.12 H.sub.11 N.sub.3       O.sub.3 (277.29Ber.:C 51.99 H 4.00N 15.16Gef.: C 52.1 H 4.0N 15.2  33       ##STR120##       ##STR121##       61 0.40 (95:5) 2133 (N.sub.3)172016551522 (NO.sub.3 as.1350 (NO.sub.2      s.) 4.19 (s, 2H, PhCH.sub.3), 5.38 (s, 2H.COOCH.sub.2), 7.2-7.5 (m, 5H,      Ph),7.52 (d, J=9 Hz, 2H, Harom.),8.25 (d, J=9 Hz, 2H, Harom.), (Schmp.:      74-76° C.)       34      ##STR122##       ##STR123##       84 0.30 (4:1) 2155 (N.sub.3)171516581516 (NO.sub.3 as1349 (NO.sub.3 s.) 3      .81,3.82 (s, 6H, OCH.sub.3 ), 4.03 (s2H, ArCH.sub.3 CO), 5.33 (s,      2H,COOCH.sub.3), 6.76 (m, 3H, Harom.),7.48 (d, J=9 Hz, 2H, Harom.),8.18      (d, J=9 Hz, 2H, Harom.). C.sub.19 H.sub.17 N.sub.3 O.sub.7 (399.4)Ber:C      57.14 H 4.29N 10.52Geb.: C 56.7 H 4.4N 10.1  34.sup.(a) CF.sub.3         C      CH.sub.3HCH.sub.3 77 0.57 (9:1) 2135 (N.sub.3)17101655       ##STR124##      .sup.(a) Preparation Example 18 + NaN.sub.3 (1.3 equivalent) in DMF 1 h      0° C.      .sup.(b) Preparation Example 18 + KSCN (1.2 equivalent ) 40 h room      temperature      .sup.(c) Preparation Example 18 + PhSNa (1.2 equivalent) in THF 3 h      0° C.

(B) Examples of the preparation of compounds of the formula I by the process according to the invention.

EXAMPLE 1 ##STR125## (3S,4R)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one

7.2 ml (52 mmol - 2.6 equivalents) of triethylamine are added to a solution, which has been cooled to 0° C., of 5.75 g (20 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one [S. Oida et al. Chem. Pharm. Bull. 29 2899 (1981); M. Shiozaki et al. Tetrahedron 39 2399 (1983)] and 4.37 g (26 mmol - 1.3 equivalents) of allyl 2-diazo-3-oxobutanoate in 190 ml of anhydrous dichloromethane, and then 9.3 ml (48 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate are added dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h, 1.55 ml (8 mmol - 0.4 equivalent) of trimethylsilyl trifluoromethanesulphonate were added, and the mixture was stirred for a further 0.5 h at room temperature. The reaction solution was then poured into a mixture of cold, saturated NaHCO.sub. 3 solution and ethyl acetate, and extraction with ethyl acetate was carried out, and the combined organic extracts were washed with saturated NaCl solution and dried over MgSO₄. The solvent was evaporated in vacuo, and the residue was filtered through 150 g of silica gel (toluene:ethyl acetate 4:1). 6.4 g (81%) of the title compound were obtained as pale crystals, melting point: 66° C., Rf: 0.33 (toluene:ethyl acetate 7:3) [α]_(D) ²⁰ =59.2° (c 0.969, CHCl₃).

IR (CHCl₃) 2144 (N₂), 1761 (C═O, β-lactam), 1714, 1649 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ 0.06 (s, 6H, CH₃ Si), 0.88 (s, 9H, CH₃ C--Si), 1.23 (d, J=6 Hz, 3H, CH₃ CH), 2.90 (dd, J=2 Hz, 5 Hz, 1H, H-3), 3.03 (dd, J=10 Hz, 17.5 Hz, 1H, CH₂ CO), 4.06 (ddd, J=3 Hz, 5 Hz, 10 Hz, 1H, H-4), 4.24 (dq, J=5 Hz, 6 Hz, 1H, CH₃ CH), 4.78 (m, 2H, CH₂ --CH═CH), 5.3-5.5 (m, 2H, CH═CH₂), 5.9-6.1 (m, CH₂ --CH═CH₂), 6.07 (bs, NH) together 2H.

C₁₈ H₂₉ N₃ O₅ Si (395.5): calculated: C 54.66, H 7.39, N 10.62. found: C 54.3, H 7.4, N 10.4.

EXAMPLE 2 ##STR126## (3S,4R)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl]azetidin-2-one

As described for Example 1, 2.02 g (82%) of the title compound were obtained as a viscous oil, Rf: 0.35 (toluene:ethyl acetate 3:2), [α]_(D) ²⁰ =44.75° (c 0.373, CHCl₃), from 1.44 g (5.0 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-t-tert.-butyldimethylsilyloxyethyl]azetidin 2-one and 1.71 g (6.5 mmol) 4-nitrobenzyl-2-diazo-3-oxo-butanoate after chromatography of the crude product on 35 g of silica gel (toluene:ethyl acetate 7:3).

IR (CHCl₃) 2160 (N₂), 1759 (C═O, β-lactam), 1722, 1655, 1520 (NO₂ as.), 1355 cm⁻¹ (NO₂ s.).

¹ H-NMR (250 MHz, CDCl₃) δ 0.006, 0.007 (s, 6H, CH₃ Si), 0.86 (s, 9H, CH₃ C--Si), 1.22 (d, J=6 Hz, 3H, CHCH₃), 2.97 (dd, J=2 Hz, 5 Hz, 1H, H-3), 3.01 (dd, J=10 Hz, 17 Hz, 1H, CH₂ CO), 3.41 (dd, J=3 Hz, 17 Hz, 1H, CH₂ CO), 4.04 (m, 1H, H-4), 4.20 (dq, J=5 Hz, 6 Hz, 1H, CH₂ CH), 5.38 (s, 2H, COOCH₂) 7.57 and 8.28 (d, J=9 Hz, each 2H, p-NO₂ --C₆ H₄).

EXAMPLE 3 ##STR127## (3S,4R)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[(1R,S)-3-allyloxycarbonyl-3-diazo-1-methyl-2-oxopropyl]-azetidin-2-one

1.8 ml (13.0 mmol - 3 equivalents) of triethylamine were added to a solution, which had been cooled to 0° C., of 1.23 g (4.28 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one and 1.18 g (6.5 mmol - 1.5 equivalents) of allyl 2-diazo-3-oxopentanoate in 48 ml of anhydrous dichloromethane, and then 2.3 ml (12 mmol - 2.8 equivalents) of trimethylsilyl trifluoromethanesulphonate were added dropwise. The cooling bath was removed, the mixture was stirred at room temperature for 4 h, 0.4 ml (2.0 mmol - 0.5 equivalent) of trimethylsilyl trifluoromethanesulphonate was added, and the mixture was stirred at room temperature for a further 1 h. Then the reaction solution was poured into a mixture of cold, saturated NaHCO₃ solution and ethyl acetate, extraction with ethyl acetate was carried out, followed by washing with saturated NaCl solution and drying over MgSO₄. The solvent was evaporated in vacuo, and the residue was chromatographed on 60 g of silica gel (toluene:ethyl acetate 4:1). 870 mg (42%) of the title compound were obtained as a 6:4 mixture of the (1R,S)-1-methyl diastereomers as pale crystals, melting point: 167° C., Rf: 0.21 (toluene:ethyl acetate 4:1).

IR (KBr) 2135 (N₂), 1761 (C═O, β-lactam), 1720 (C═O), 1657 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ 0.07, 0.08 (s, 6H, CH₃ Si), 0.86, 0.87 (s, 9H, CH₃ C--Si), 1.18, 1.20 (d, J=7 Hz, 3H, CH₃ CH), 1.22, 1.26 (d, J=7.5 Hz, 3H, CH₃ CHOSi), 2.82, 2.98 (dd, J=2 Hz, 5Hz, 1H, H-3), 3.58 3.90 (m, 1H, CH₃ CH), 3.92 (m, 1H, H-4), 4.20 (m, 1H, CH₃ CHOSi), 4.75 (m, 2H, CH₂ --CH═CH₂), 5.3-5.4 (m, 2H, CH═CH₂), 5.81, 5.91 (bs, 1H, NH), 5.9-6.1 (m, 1H, --CH₂ --CH═CH₂).

EXAMPLE 4 ##STR128## 4-(3-Allyloxycarbonyl-3-diazo-2-oxopropyl)azetidine-2-one

As described for Example 1, 3.60 g (76%) of the title compound were obtained as pale crystals, melting point: 83° C., Rf: 0.26 (toluene:ethyl acetate 1:4), from 2.58 g (20.0 mmol) of 4-acetoxy-2-azetidinone [German Patent Specification No. 1,906,401 - 08.02.1969] and chromatography of the crude product on 200 g of silica gel (toluene:ethyl acetate 1:3).

IR (KBr) 2150 (N₂), 1771 (C═O, β-lactam), 1701, 1634 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ 2.69 (dd, J=1 Hz, 14.5 Hz, 1H, H-3β), 3.04 (dd, J=10 Hz, 18 Hz, 1H, CH₂ CO), 3.19 (ddd, J=1 Hz, 5 Hz, 14.5 Hz, 1H, H-3α), 3.40 (dd, J=5 Hz, 18 Hz, 1H, CH₂ CO), 4.01 (m, 1H, H-4), 4.76 (m, 2H, CH₂ --CH═CH₂), 5.3-5.4 (m, 2H, --CH═CH₂), 5.9-6.1 (m, 1H, CH₂ --CH═CH₂), 6.10 (bs, 1H, NH).

C₁₀ H₁₁ N₃ O₄ (237.2): calculated: C 50.63, H 4.67, N 17.71. found: C 50.2, H 4.7, N 16.8.

EXAMPLE 5 ##STR129## 4-(3-Diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl)azetidin-2-one

(a) As described for Example 1, 1.12 g (67%) of the title compound is obtained as colorless crystals, melting point: 104° C., Rf: 0.29 (ethyl acetate), from 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.71 g (6.5 mmol) of 4-nitrobenzyl 2-diazo-3-oxobutanoate and chromatography of the crude product on 27 g of silica gel (toluene:ethyl acetate 3:2).

IR (KBr) 2145 (N₂), 1767 (C═O, β-lactam, 1969, 1653, 1528 (NO₂ as.), 1349 cm⁻¹ (NO₂ s.).

¹ H-NMR (250 MHz, CDCl₃) δ 2.70 (dd, J=1 Hz, 17.5 Hz, 1H, H-3β), 3.08 (dd, J=9.5 Hz, 18 Hz, 1H, CH₂ CO), 3.20 (ddd, J=1.5 Hz, 5 Hz, 17.5 Hz, 1H, H-3α), 3.40 (dd, J=5 Hz, 18 Hz, 1H, CH₂ CO), 4.04 (m, 1H, H-4), 5.42 (s, 2H, COOCH₂), 7.59 and 8.42 (d, J=10 Hz, each 2H, p-NO₂ --C₆ H₄)

C₁₄ H₁₂ N₄ O₆ (332.3): calculated: C 50.61, H 3.64, N 16.86. found: C 50.6, H 3.6, N 16.7.

(b) 2.32 ml (13.0 mmol) of ethyldiisopropylamine and then 2.3 ml (12 mmol) of trimethylsilyl trifluoromethanesulphonate were added to a solution, which had been cooled to 0° C., of 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.71 g (6.5 mmol) of 4-nitrobenzyl 2-diazo-3-oxobutanoate in 48 ml of anhydrous THF. The cooling bath was removed and the mixture was stirred at room temperature for 1 h, then 0.3 ml (1.5 mmol) of trimethylsilyl trifluoromethanesulphonate was added, and the mixture was stirred at room temperature for 1 h and worked up as described in Example 1. After chromatography of the crude product on 90 g of silica gel (ethyl acetate), 950 mg (57%) of the title compound were obtained as colorless crystals, melting point 103°-104° C. The other physical data were identical to those of the substance obtained by method (a).

EXAMPLE 6 ##STR130## 4-(3-Diazo-1-methoxy-3-methoxycarbonyl-2-oxopropyl)azetidin-2-one

As described for Example 1, the title compound was obtained as a 5:1 mixture of diastereomers which could not be separated, Rf: 0.19 (toluene:ethyl acetate 1:9), from 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.12 g (6.5 mmol) of methyl 2-diazo-4-methoxy-3-oxobutanoate after 4 h at room temperature and chromatography of the crude product on 60 g of silica gel (toluene:ethyl acetate 1:9).

IR (CHCl₃) 2150 (N₂), 1560 (C═O), β-lactam 1720 1660 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃), predominant diastereomer δ 2.93 (dd, J=4.5 Hz, 15 Hz, 1H, H-3), 3.07 (dd, J=1.5 Hz, 15 Hz, 1H, H-3β), 3.46 (s, 3H, OCH₃), 3.90 (s, 3H, COOCH₃), 3.95 (m, 1H, H-4), 4.90 (d, J=4.5 Hz, 1H, CH--CH--OCH₃), 6.00 (bs, 1H, NH).

EXAMPLE 7 ##STR131## 4-(3-tert.-Butyloxycarbonyl-1-chloro-3-diazo-2-oxopropyl)azetidin-2-one

1.8 ml (13.0 mmol - 2.6 equivalents) of triethylamine and then 2.3 ml (12.0 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate were added to a solution, which had been cooled to 0° C., of 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.42 g (6.5 mmol) of tert.-butyl 4-chloro-2-diazo-3-oxobutanoate in 45 ml of anhydrous dichloromethane. The cooling bath was removed and the mixture was stirred at room temperature for 5 h, then 0.3 ml (1.5 mmol - 0.3 equivalent) of trimethylsilyl trifluoromethanesulphonate was added and the mixture was stirred at room temperature for 1 h. To work up, it was poured into a mixture of cold saturated NaHCO₃ solution and ethyl acetate, extraction with ethyl acetate was carried out, and the organic extracts were washed with saturated NaCl solution and dried over MgSO₄. After evaporation of the solvent in vacuo and chromatography on 40 g of silica gel (toluene:ethyl acetate 1:1), 426 mg (30%) of the title compound were obtained as a mixture of diastereomers (10:1), Rf: 0.35 (toluene:ethyl acetate 1:1).

IR (CHCl₃) 3419 (NH), 2143 (N₂), 1770 (C═O, β-lactam), 1711, 1648 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ 1.56 (s, 9H, C(CH₃)₃), 2.95 (dd, J=1.5 Hz, 15 Hz, 1H, H-3β, 3.24 (ddd, J=2.5 Hz, 5 Hz, 15.5 Hz, 1H, H-3α), 4.15 (m, 1H, H-4), 5.20 (d, J=9 Hz, 1H, CH--CHCl), 6.05 (bs, 1H, NH).

C₁₁ H₁₄ ClN₃ O₄ (287.7): calculated: C 45.92, H 4.91. found: C 46.2, H 5.1.

EXAMPLE 8 ##STR132## 4-(1-Benzyloxy-3-tert.-butoxycarbonyloxy-3-diazo-2-oxopropyl)azetidin-2-one

As described for Example 7, the title compound was obtained as a mixture of the two diastereomers in the ratio >9:1, Rf: 0.56 (toluene:ethyl acetate 1:9), from 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.89 g (6.5 mmol) of tert.-butyl 4-benzyloxy-2-diazo-3-oxobutenoate and chromatography of the crude product on 150 g of silica gel.

IR (CHCl₃) 2145 (N₂), 1765 (C═0, β-lactam), 1705, 1650 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ1.50 (s, 9H, C(CH₃)₃), 2.90 ddd, J=2 Hz, 5 Hz, 16 Hz, 1H, H-3α), 3.09 (dd, J=1 Hz, 16 Hz, 1H, H-3β), 3.92 (m, 1H, H-4), 4.48, 4.72 (AB, J=11 Hz, 2H, OCH₂ Ph), 5.08 (d, J=4.5 Hz, 1H, CHCHOCH₂ Ph), 6.03 (bs, 1H, NH).

EXAMPLE 9 ##STR133## (3s,4R)-3-[(1R)-1-Allyloxycarbonyloxyethyl]-4-[3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one

As described for Example 1, 226 mg (36%) of the title compound were obtained as an oil, Rf: 0.26 (toluene: ethyl acetate 3:2), from 447 mg (1.74 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-allyloxycarbonyloxyethyl]azetidin-2-one and 380 mg (2.26 mmol) of allyl 2-diazo-3-oxobutanoate after chromatography of the crude product on 30 g of silica gel (toluene:ethyl acetate 3:2).

IR (CHCl₃) 2150 (N₂), 1755 (C═0, β-lactam), 1720 1645 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ1.44 (d, J=6.5 Hz, 3H, CH₃ CH), 3.03 (dd, J=9.5 Hz, 18 Hz, CH₂ CO), 3.08 (m, H-6) together 2H, 3.44 (dd, J=4.5 Hz, 18 Hz, 1H, CH₂ CO), 4.0 (m, 1H, H-5), 4.62 (m, 2H, --CH₂ --CH═CH₂), 4.74 (m, 2H, --CH₂ --CH═CH₂), 5.11 (dq, J=6.5 Hz, 7 Hz, 1H, CH₃ CHO), 5.25-5.4 (m, 4H, CH═CH₂), 5.9-6.0 (m, 2H, CH═CH₂), 6.14 (bs, 1H, NH).

EXAMPLE 10 ##STR134## 4-(1-Acetylthio-3-tert.-butoxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one

As described for Example 7, 348 mg (21%) of the title compound were obtained as a mixture of the two diastereomers in the ratio 2:1, Rf: 0.22 (toluene:ethyl acetate 3:2), from 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.67 g (6.5 mmol) of tert.-butyl 4-acetylthio-2-diazo-3-oxobutanoate and chromatography of the crude product on 50 g of silica gel (toluene:ethyl acetate 3:2).

IR (CHCl₃) 2140 (N₂), 1765 (C═0, β-lactam), 1713 1641 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ1.52, 1.53 (s, 9H, C(CH₃)₃), 2.38 (s, 3H, COCH₃), 2.7-3.1 (m, 2H, H-3, H-3'), 4.10 (m, 1H, H-4), 5.45 (d, J=6 Hz), 5.58 (d, J=5 Hz, CH--CHSCOCH₃ together 1 H, 5.92, 6.10 (bs, 1H, NH).

EXAMPLE 11 ##STR135## 4-(1-Benzylthio-3-tert.-butoxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one

As described for Example 7, 410 mg (22%) of the title compound were obtained as a mixture of the two diastereomers in the ratio 3:1, crystals, melting point: 119° C., Rf: 0.31 (toluene:ethyl acetate 3:2), from 646 mg (5.0 mmol) of 4-acetoxy-2-azetidinone and 1.99 g (6.5 mmol) of tert.-butyl 4-benzylthio-2-diazo-3-oxobutanoate after chromatography of the crude product on 180 g of silica gel (toluene:ethyl acetate 3:2).

IR (CHCl₃) 2140 (N₂), 1758 (C═0, β-lactam), 1705, 1632 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ1.56, 1.57 (s, 9H, C(CH₃)₃), 2.52 (dd, J=15 Hz, 1.5 Hz, 1H, 3-Hβ), 2.92 (ddd, J=15 Hz, 4.5 Hz, 3 Hz, 1H, 3-H), 3.78, 3.89 (AB, J=14.5 Hz, 2H, SCH₂ Ph), 4.0 (m, 1H, H-4), 4.47 (d, J=10 Hz, CHSCH₂ Ph), 4.63 (d, J=8 Hz, CHSCH₂ Ph), together 1H, 5.62, 5.70 (bs, 1H, NH), 7.4 (m, 5H, Ph).

C₁₈ H₂₁ N₃ O₄ S: calculated: C 57.58, H 5.64, N 11.19, S 8.54, found: C 57.2, H 5.6, N 10.7, S 8.7,

EXAMPLE 12 ##STR136## (3S,4S)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[[1R)-3-allyloxycarbonyl-1-chloro-3-diazo-2-oxopropyl]-azetidin-2-one and (3S,4S)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[(1S)-3-allyloxycarbonyl-1-chloro-3-diazo-2-oxopropyl]azetidin-2-one

As described for Example 7, 171 mg (8%) of the unpolar isomer are obtained as colorless crystals, melting point: 104° C., Rf: 0.38 (toluene:ethyl acetate 4:1), from 1.44 g (5.0 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one and 1.32 g (6.5 mmol) of ally 4-chloro-2-diazo-3-oxobutanoate and chromatography of the crude product on 240 g of silica gel (toluene:ethyl acetate 85:15).

IR (KBr) 2145 (N₂), 1769 (C═0, β-lactam), 1720, 1662 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) 0.08 (s, 6H, CH₃ Si), 0.87 (s, 9H, CH₃ C-Si), 1.20 (d, J=6.3 Hz, 3H, CH₃ CH), 3.07 (m, 1H, H-3), 4.08 (dd, J=2.3 Hz, 4.3 Hz, 1H, H-4), 4.17 (dq, J=3.8 Hz, 6.3 Hz, 1H, CH₃ CHOSi), 4.70 (d, J=5.8 Hz, 2H, CH₂ --CH=CH₂), 5.3-5.4 (m, 2H, CH═CH₂), 5.50 (d, J=4.3 Hz, 1H, CHCl), 5.8-6.0 (m, 1H, --CH₂ --CH=CH₂), 6.0 (bs, 1H, NH).

In addition, 755 mg (35%) of the polar isomer were obtained as colorless crystals, melting point: 107° C., Rf: 0.27 (toluene:ethyl acetate 4:1).

IR (K8r) 2140 (N₂), 1768 (C═0, β-lactam), 1720, 1671 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ0.08, 0.09 (s, 6H, CH₃ Si), 0.88 (s, 9H, CH₃ C-Si), 1.24 (d, J=6.3 Hz, 3H, CH₃ CH), 3.08 (dd, J=2.3 Hz, 2.4 Hz, 1H, H-3), 4.26 (dd, J=2 Hz, 8.9 Hz, H-4), 4.3 (m, CH₃ CHOSi) together 2H, 4.79 (m, 2H, CH₂ --CH═CH₂), 5.20 (d, J=8.9 Hz, 1H, CHCl), 5.3-5.4 (m, 2H, CH═CH₂), 5.86 (bs, NH), 5.8-6.0 (m, --CH₂ --CH═CH₂) together 2H.

EXAMPLE 13 ##STR137## (3S,4R)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[(1R)-3-allyloxycarbonyl-3-diazo-2-oxo-1-phenylpropyl]-azetidin-2-one and (3S,4R)-3-[1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[(1S)-3-allyloxycarbonyl-3-diazo-2-oxo-1-phenylpropyl]-azetidin-2-one

As described for Example 7, 200 mg (9%) of the unpolar title compound are obtained as an oil, Rf: 0.32 (toluene:ethyl acetate 4:1), from 1.44 g (5.0 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-azetidin-2-one and 1.59 g (6.5 mmol) of allyl 2-diazo-3-oxo-4-phenylbutanoate and chromatography of the crude product on 230 g of silica gel (toluene:ethyl acetate 4:1).

IR (CHCl₃) 2140 (N₂), 1760 (C═0, β-lactam), 1720, 1650 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ0.07, 0.08 (s, 6H, CH₃ Si), 0.88 (s, 9H, CH₃ C-Si), 1.19 (d, J=6.3 Hz, 3H, CH₃ CH), 2.68 (m, 1H, H-3), 4.18 (m, CH₃ CHOSi), 4.24 (dd, J=2.5 Hz, 6.5 Hz, H-4) together 2H, 4.6-4.8 (m, 2H, CH₂ --CH═CH₂), 4.97 (d, J=6.5 Hz, 1H, CHPh), 5.2-5.4 (m, 2H, CH═CH₂), 5.83 (bs, NH), 5.8-6.0 (m, CH₂ --CH═CH₂) together 2H, 7.35 (m, 5H, Ph).

In addition, 530 mg (22%) of the polar title compound were obtained as colorless crystals, melting point: 139° C., Rf: 0.21 (toluene:ethyl acetate 4:1).

IR (KBr) 2138 (N₂), 1764 (C═0, β-lactame), 1725, 1658 cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ0.01 (s, 6H, CH₃ Si), 0.25 (d, J=6 Hz, 3H, CH₃ CH), 0.88 (s, 9H, CH₃ C-Si), 2.84 (m, 1H, H-3), 4.09 (m, 1H, CH₃ CHOSi), 4.36 (dd, J=2.3 Hz, 10.5 Hz, H-4), 4.66 (m, --CH₂ --CH═CH₂), 4.73 (d, J=10.5 Hz, CHPh) together 2H, 5.2-5.4 (m, 2H, CH═CH₂), 5.9-6.0 (m, CH₂ --CH═CH₂), 5.94 (bs, NH) together 2H, 7.34 (m, 5H, Ph).

EXAMPLE 14 ##STR138## (3S,4S)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[(1R)-1-acetylthio-3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one and (3S,4S)-3-[(1R)-1-tert.-Butyldimethylsilyloxyethyl]-4-[(1S)-1-acetylthio-3-allyloxycarbonyl-3-diazo-2oxopropyl]azetidin-2-one

As described for Example 7, 457 mg (15%) of the unpolar title compound were obtained as an oil, Rf: 0.40 (toluene:ethyl acetate 7:3), from 2.70 g (9.4 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one and 2.96 g (12.2 mmol) of allyl 4-acetylthio-2-diazo-3-oxobutanoate and chromatography of the crude product on 650 g of silica gel (toluene:ethyl acetate 4:1).

IR (CHCl₃) 2135 (N₂), 1765 (C═0, β-lactam), 1715, 1638 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ0.07, 0.08 (s, 6H, CH₃ Si), 0.87 (s, 9H, CH₃ c--Si), 1.22 (d, J=6.5 Hz, 3H, CH₃ CH), 2.39 (s, 3H, SCOCH₂), 2.92 (m, 1H, H-3), 4.18 (m, H-4), 4.23 (m, CH₃ CHOSi) together 2H, 4.75 (m, 2H, --CH₂ --CH═CH₂), 5.3-5.4 (m, CH═CH₂), 5.61 (d, J=4 Hz, 1H, CHSCOCH₃), 5.8-6.0 (m, --CH₂ --CH═CH₂), 5.98 (bs, NH) together 2H.

In addition, 1.5 g (48%) of the polar title compound was obtained as an oil, Rf: 0.36 (toluene:ethyl acetate 7:3).

IR (CHCl₃) 3350 (NH), 2140 (N₂), 1758 (C═0, β-lactam), 1715, 1640 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ0.07 (s, 6H, CH₃ Si), 0.88 (s, 9H, CH₃ C-Si), 1.19 (d, J=6.5 Hz, 3H, CH₃ CH), 2.37 (s, 3H, SCOCH₃), 3.12 (m, 1H, H-3), 4.20 (dd, J=2 Hz, 7.5 Hz, H-4), 4.20 (m, CH₃ CHOSi) together 2H, 4.75 (m, 2H, --CH₂ --CH═CH₂), 5.3-5.4 (m, 2H, --CH═CH₂), 5.42 (d, J=7.5 Hz, 1H, CHSCOCH₃), 5.80 (bs, 1H, NH), 5.85-6.0 (m, 1H, CH₂ --CH═CH₂).

EXAMPLE 15 ##STR139## (3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R,S)-1-acetylthio-3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one

1.15 ml (8.3 mmol - 3.6 equivalents) of triethylamine and then 1.51 ml (7.8 mmol - 3.4 equivalents) of trimethylsilyl trifluoromethanesulphonate were added to a solution, which had been cooled to 0° C., of 400 mg (2.3 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-hydroxyethyl]azetidin-2-one and 720 mg (3.0 mmol) of allyl 4-acetylthio-2-diazo-3-oxobutanoate in 20 ml of anhydrous dichloromethane. The cooling bath was removed, the mixture was stirred at room temperature for 4 h, 133 μl (0.7 mmol - 0.3 equivalent) of trimethylsilyl trifluoromethanesulphonate were added, and the mixture was stirred at room temperature for 3 h and worked up as described in Example 1. After chromatography of the crude product on 40 g of silica gel (ethyl acetate), the title compound was obtained as a mixture of the two diastereomers which could not be separated, Rf: 0.31 (ethyl acetate).

IR (CHCl₃) 3380 (NH, 2150 (N₂), 1758 (C═0, β-lactam), 1720, 1642 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ1.30, 1.32 (d, J=6.3 Hz, 3H, CH₃ CH), 2.25, 2.75 (bs, 1H, OH), 2.40 (s, 3H, SCOCH₃), 2.96, 3.14 (m, 1H, H-3), 4.14 (m, 2H, H-4, CH₃ CHOH), 5.25 (m, 2H, CH₂ --CH═CH₂), 5.3-5.4 (m, 2H, CH═CH₂), 5.50 (d, J=6Hz, CHSCOCH₃), 5.45 (d, J=4.8 Hz, CHSCOCH₃) together 1H, 5.85-6.05 (m, 1H, CH₂ --CH═CH₂), 6.15 (bs, 1H, NH).

EXAMPLE 16 ##STR140## (3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[3-diazo-3-p-nitrobenzyl-oxycarbonyl-2-oxopropyl]azetidin-2-one

10 mg (0.02 mmol) of (3S,4R)-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-4-[3-p-nitrobenzyloxycarbonyl-2-oxopropyl]azetidin-2-one were dissolved, at 0° C., in 1 ml of a standard solution of 3.76 μl (0.03 mmol - 1.5 equivalents) of boron trifluoride etherate in acetonitrile, and the mixture was stirred at this temperature for 2 h. The reaction solution was then filtered through 0.5 g of silica gel/NaHCO₃ and evaporated in vacuo, and the title compound was obtained, Rf: 0.24 (toluene:ethyl acetate 1:9).

IR (CHCl₃) 3419 (OH), 2142 (N₂), 1768 cm⁻¹ (C═0, β-lactam).

¹ H-NMR (250 MHz, CDCl₃) δ1.35 (d, J=6.5 Hz, 3H, CH₃ CH), 1.62 (bs, 1H, OH), 2.91 (dd, J=1.5 Hz, 7.5 Hz, 1H, H-6), 3.22 (dd, J=7.5 Hz, 19 Hz, 1H, CH₂ CO), 3.35 (dd, J=7.5 Hz, 19 Hz, 1H, CH₂ CO), 4.00 (m, 1H, H-5), 4.20 (dq, J=6.5 Hz, 7.5 Hz, 1H, CH₃ CHOH), 5.40 (s, 2H, COOCH₂), 6.00 (bs, 1H, NH), 7.58 and 8.30 (d, J=9 Hz, each 2H, p--NO₂ --C₆ H₄).

The compound of this example has been used as an intermediate for the synthesis of thienamycin [U.S. Pat. No. 4,290,947: Th. N. Salzmann et al. J. Am. Chem. Soc. 102 6163 (1980)].

PREPARATION EXAMPLE 17 ##STR141## (3S,4R)-3-tert.-Butyldimethylsilyloxymethyl]-4-[3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one

0.72 ml (5.2 mmol) of triethylamine and then, dropwise, 0.93 ml (4.8 mmol) of trimethylsilyl trifluoromethanesulphonate were added to a solution, which had been cooled to 0° C., of 547 mg (2.0 mmol) of (3R,4R)-4-acetoxy-3-[tert.-butyldimethylsilyloxymethyl]azetidin-2-one and 437 mg (2.6 mmol) of allyl 2-diazo-3-oxobutanoate in 18 ml of anhydrous dichloromethane. The cooling bath was removed, the mixture was stirred at room temperature for 15 min, 0.12 ml (0.6 mmol) of trimethylsilyl trifluoromethanesulphonate was added, and the mixture was stirred at room temperature for a further 15 min. The reaction solution was then poured into a mixture of cold, saturated NaHCO₃ solution and ethyl acetate, extraction with ethyl acetate was carried out, and the organic extracts were washed with saturated NaCl solution and dried over MgSO₄. The solvent was evaporated in vacuo and the residue was chromatographed on 50 g of silica gel (toluene:ethyl acetate 4:1). 462 mg (61%) of the title compound were obtained as an oil, Rf: 0.11 (toluene:ethyl acetate 4:1).

IR (CHCl₃) 3380 (NH), 2150 (N₂), 1760 (C═0, β-lactam), 1715, 1648 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ0.07 (s, 6H, CH₃ Si), 0.88 (s, 9H, CH₃ CSi), 3.03 (m, 1H, H-3), 3.11 (dd, J=10 Hz, 18 Hz, 1H, CH₂ CO), 3.40 (dd, J=5 Hz, 18 Hz, 1H, CH₂ CO), 3.95 (m, H-4), 4.0 (m, CH₂ OSi) together 3H, 4.76 (m, 2H, CH₂ --CH═CH₂), 5.3-5.45 (m, 2H, --CH═CH₂), 5.9-6.1 (m, --CH₂ --CH═CH₂), 6.01 (bs, NH) together 2H.

EXAMPLE 18 ##STR142## (3S,4R)-3-[tert.-Butyldimethylsilyloxymethyl]-4-[3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl]azetidin-2-one

As described for Example 17, 1.22 g (65%) of the title compound were obtained as colorless crystals, melting point: 104° C., Rf: 0.31 (toluene:ethyl acetate 1:1), from 930 mg (3.4 mmol) of (3R,4R)-4-acetoxy-3-[tert.-butyldimethylsilyloxymethyl]azetidin-2-one and 1.16 g (4.42 mmol - 1.3 equivalents) of 4-nitrobenzyl 2-diazo-3-oxobutanoate after chromatography of the crude product on 100 g of silica gel (toluene:ethyl acetate 1:1).

IR (KBr) 3352 (NH), 2139 (N₂), 1755 (C═0, β-lactam), 1713, 1660, 1525 (NO₂ as.), 1349 cm⁻¹ (NO₂ s.).

¹ H-NMR (300 MHz, CDCl₃) δ0.06 (s, 6H, CH₃ Si), 0.86 (s, 9H, CH₃ CSi), 2.98 (m, 1H, H-3), 3.05 (dd, J=9 Hz, 18 Hz, 1H, CH₂ CO), 3.34 (dd, J=5 Hz, 1H, CH₂ CO), 3.89 (m, 1H, H-4), 3.96 (m, 2H, CH₂ OSi), 5.31 (s, 2H, COOCH₂), 5.93 (bs, 1H, NH), 7.50 (d, J=9 Hz, 2H, H_(arom).), 8.23 (d, J=9 Hz, 2H, H_(arom).).

As described in Example 7, the following compounds (Example 19-24, Table 3) were obtained by reaction of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one with the corresponding diazoacetoacetic esters: ##STR143## (The time column represents the stirring time at room temperature after addition of the catalytic amount of trimethylsilyl trifluoromethanesulphonate).

    TABLE 3       Example   Time Rf IR .sup.1       HNMR  No. R.sup.3 R.sup.4 (h) (Tol.:Ethylac.) (cm.sup.-1) (250 MHz,      CDCl.sub.3) δ       ppm Notes                                              19 SCH CH.sub.2CHC      H.sub.2 2 0.14, 0.18 3416 fd: (NH) (s, 6H, CH.sub.2 Si), C.sub.19      H.sub.20 N.sub.4 O.sub.3 SSi     (4:1) 2155 (N.sub.2) 0.88 (s, 9H,      CH.sub.2       CSi), (452.61)              1775 (C O)      ##STR144##       calc: C 50.42 N 6.24      1714 3.0-3.2 (m, 1H, N3),  N 12.38 S 7.08       1652       ##STR145##       fd: C 50.5 N 6.3       4.68 (d, J=10 Hz, CHSCN),  N 12.4 S 7.0      5.19 (d, J=5.5 Hz, CHSCN), together 1N, diastereomers       ##STR146##       about 3:2       ##STR147##       ##STR148##             6.18, 6.60 (bs, 1H, NH).  20 N.sub.2 CH.sub.2CHCH.sub.2 2 0.25      (4:1) 3395 (NH) 0.08, 0.09 (s, 6H, CH.sub.2 Si), diastereomers      2130      (N.sub.2) 0.89 (s, 9H, CH.sub.2 CSi), about 1:1      2115 (N.sub.2)       ##STR149##            1762 (CO) 3.14 (m, 1H, H3),      1718 4.13 (dd, J=2Hz, 9Hz, 1H,      H4),      1658       ##STR150##       ##STR151##             5.03 (d, J=9Hz, 1H, CHN.sub.3),       ##STR152##             5.77 (bs, 1H, NH),       ##STR153##        21 PhS CH.sub.2CHCH.sub.2 7 0.23 (9:1) 3380 (NH) 0.07, 0.08 (s, 6H,      CH.sub.2 Si), diastereomers      2140 (N.sub.2) 0.88 (s, 9H, CH.sub.2      CSi),      1761 (CO)       ##STR154##            1645 3.08 (m, 1H, H3),       ##STR155##             4.46 (d, J=9Hz, CHSPh),       ##STR156##             together 3H.       ##STR157##       ##STR158##             6.08, 6.15 (bs, 1H, NH).       22      ##STR159##       CH.sub.2CHCH.sub.2 650°       C. 0.29 (7:3) 3385 (NH)2145 (N.sub.2)1770 (CO)17181645       ##STR160##       Diastereomersabout 8:1       23      ##STR161##       CH.sub.2CHCH.sub.2 66 0.06 (0:1) 3341 (NH)2140 (N.sub.2)1772 (CO)1715165      01250       ##STR162##       Diastereomers  24 COOCH.sub.2CHCH.sub.2 CH.sub.2CHCH.sub.2 5.5 0.29,      0.25 3395 (NH) 0.05 (s, 6H, CH.sub.2 Si), Diastereomers     (4:1) 2152      (N.sub.2) 0.86, 0.87 (s, 9H, CH.sub.2       C Si), 1:1      1760 (CO)      ##STR163##            1720 3.21, 3.24 (m, 1H, H3).      1650       ##STR164##             4.34 (m, H4) together 2H,       4.66 (d, J=7Hz, CHCOO),       ##STR165##       ##STR166##       ##STR167##             5.92, 6.10 (bs, NH) together 3H.       25 CH.sub.2      ##STR168##       1,5 0.26 (7:3) 3350 (NH)2150 (N.sub.2)1775 (CO)17251525 (NO.sub.2      as.1355 (NO.sub.2 s.)       ##STR169##       Diastereomers1'(R):1'(S) = 2:3       26      ##STR170##       ##STR171##       15 0.23 (7:3) 3350 (NH)2148 (N.sub.2)1762 (CO)17201530 (NO.sub.2      as.1555 (NO.sub.2 s.) 0.01, 0.04, 0.06, 0.08 (s, 6H,CH.sub.2 Si), 0.25,      1.20 (d, J=6Hz, 3H,CH.sub.2 CHO), 0.88 (s, 9H, CH.sub.2 CSi),2.7-3.0 (m,      1H, H3), 3.90 (m,H4), 4.35 (dd, J=2Hz, 10Hz,H4) tog. 1H, 4.15 (m,      1H,CH.sub.3       CHO), 4.68 (d, J=10Hz, PhCH),5.18, 5.30 (d, 2H, COOCH.sub.2), 5.915.95      (bs, 1H, NH.sub.2) 7.2-7.35 (m,5H, Ph), 7.43 (d, J=9Hz, 2H,Harom.), 8.20      (d, J=9Hz, 2H,Harom.). Diastereomers45:55

(C) Examples for the use of compounds of the general formula I for the preparation of carbapenem antibiotics.

EXAMPLE 1 ##STR172## (2S,5R,6S)-2-Allyloxycarbonyl-3,7-dioxo-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-1-azabicyclo[3.2.0]heptane

A solution of 3.96 g (10 mmol) of (3S,4R)-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-4-[3-allyloxycarbonyl-3-diazo-2-oxopropyl]azetidin-2-one in 50 ml of anhydrous dichloromethane was heated to reflux for 30 minutes in the presence of 40 mg (1 mol-%) of rhodium(II) acetate. The reaction solution was filtered through a little kieselguhr and silica gel and evaporated in vacuo. 3.5 g (95%) of the title compound were obtained as a colorless oil, Rf: 0.46 (toluene:ethyl acetate 7:3).

IR (CHCl₃) 1766, 1740 cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ0.06 s, 6H, CH₃ Si), 0.87 (s, 9H, CH₃ C-Si), 1.26 (d, J=6.5 Hz, 3H, CH₃ CH), 2.44 (dd, J=8 Hz, 19 Hz, 1H, CH₂ CO), 2.88 (dd, J=8 Hz, 19 Hz, 1H, CH₂ CO), 3.15 (dd, J=2 Hz, 1H, H-6), 4.16 (ddd, J=2 Hz, 8 Hz, 8 Hz, 1H, H-5), 4.33 (dq, J=5 Hz, 6.5 Hz, 1H, CH₃ CH), 4.65 (m, 2H, CH₂ --CH═CH₂), 4.71 (s, 1H, H-2), 5.25-5.4 (m, 2H, CH═CH₂), 5.8-6.0 (m, 1H, CH₂ --CH═CH₂).

EXAMPLE 2 ##STR173## Allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]carbapen-2-em-3-carboxylate

1.94 ml (13 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) and, after 20 minutes, 2.2 ml (13 mmol) of trifluoromethanesulphonic anhydride were added dropwise to a solution, which had been cooled to -78° C., of 3.68 g (10 mmol) of (2S,5R,6S)-2-allyloxycarbonyl-3,7-dioxo-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-1-azabicyclo[3.2.0]heptane in 100 ml of anhydrous THF. The mixture was then stirred at -78° C. for 30 minutes and the solution was concentrated in vacuo to about 40 ml without the temperature rising above -20° C. Then, successively 20 ml of DMF, 2.1 ml (12 mmol) of ethyl diisopropylamine and 1.33 g (12 mmol) of 4-mercaptopyridine were added and the mixture was stirred at -20° C. for 1 h. The mixture was then diluted with ethyl acetate and poured into cold, saturated NaHCO₃ solution. Extraction was carried out with ethyl acetate, followed by washing with saturated NaCl solution and drying with MgSO₄. After evaporation of the solvent in vacuo and chromatography of the residue on 600 g of silica gel (toluene:ethyl acetate), 3.1 g (66%) of the title compound were obtained as a viscous oil, Rf: 0.30 (toluene:ethyl acetate 7:3).

IR (CHCl₃) 1781 (C═0, β-lactam), 1710 cm⁻¹ (C═0, ester).

¹ H-NMR (250 MHz, CDCl₃) δ0.02, 0.04 (s, 6H, CH₃ Si), 0.84 (s, 9H, CH₃ C-Si), 1.10 (d, J=6.5 Hz, CH₃ CH), 2.86 (dd, J=11 Hz, 18 Hz, 1H, H-1), 3.04 (dd, J=9 Hz, 18 Hz, 1H, H-1'), 3.48 (m, 1H, H-6), 4.17 (m, 2H, H-5, CH₃ CH), 4.73 (m, 2H, CH₂ --CH═CH), 5.25 (dd, J=1 Hz, 10.5 Hz, 1H, CH═CH₂ --cis), 5.47 (dd, J=1 Hz, 17 Hz, 1H, CH═CH₂ -trans), 5.9-6.1 (m, 1H, CH₂ --CH═CH₂), 7.63 (d, J=5.5 Hz, 2H, 3.5-pyridyl-H), 8.62 (d, J=5.5 Hz, 2H, 2,6-pyridyl-H).

EXAMPLE 3 ##STR174## Allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate

3.69 ml (64.5 mmol - 10 equivalents) of glacial acetic acid and 19.3 ml (19.3 mmol - 3 equivalents) of a 1M solution of tetrabutylammonium fluoride in THF were added to a solution, which had been cooled to 0° C., of 2.97 g (6.5 mmol) of allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]carbapen-2-em-3-carboxylate in 60 ml of THF. The cooling bath was removed and the reaction solution was allowed to stand at room temperature for 62 h. To work up, it was poured a into a mixture of cold, saturated NaHCO₃ solution and ethyl acetate, extraction with ethyl acetate was carried out, followed by washing with saturated NaHCO₃ and NaCl solutions and drying over MgSO₄. After evaporation of the solvent in vacuo and chromatography of the residue on 360 g of silica gel (toluene:ethyl acetate 9:1), 472 mg (21%) of the title compound were obtained as an oil, Rf: 0.24 (toluene:ethyl acetate 9:1).

IR (CHCl₃) 3400 (OH), 1776 (C═0, β-lactam) 1720 cm⁻¹ (C═0, ester).

¹ H-NMR (250 MHz, CDCl₃) δ1.32 (d, J=6.5 Hz, 3H, CH₃ CH), 2.78, 2.90 (dd, J=10 Hz, 18 Hz, 2H, H-1), 3.16 (dd, J=2.5 Hz, 7 Hz, 1H, H-6), 4.2 (m, 2H, H-5, CH₃ CH), 4.75, 4.87 (dd, J=7.5 Hz, 14.5 Hz, 2H, CH₂ --CH═CH₂), 5.30 (d, J=9 Hz, 1H, CH═CH₂ -cis), 5.48 (d, J=17 Hz, 1H, CH═CH₂ -trans), 5.9-6.1 (m, 1H, --CH₂ --CH═CH₂), 7.43 (d, J=7 Hz, 2H, 3,5-pyridyl-H), 8.64 (d, J=7 Hz, 2H, 2,6-pyridyl-H).

EXAMPLE 4 ##STR175## Sodium (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate

2.8 ml (1.4 mmol - 1.05 equivalents) of 0.5 M sodium 2-ethylhexanoate in ethyl acetate, 35 mg (0.13 mmol - 0.1 equivalent) of triphenylphosphine and 35 mg (0.03 mmol) of tetrakis-(triphenylphosphine)-palladium (0) were successively added to a solution of 462 mg (1.33 mmol) of allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate in 3.4 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 1 h. It was then diluted with 20 ml of anhydrous acetone. The precipitate was filtered off with suction and vigorously stirred with 50 ml of ether for 0.5 h, again filtered off with suction and dried over P₄ O₁₀ under high vacuum. 361 mg (83%) of the title compound were obtained as a colorless hygroscopic powder.

IR (KBr) 3400 (OH), 1755 (C═0,β-lactam), 1600 (COONa), 1576, 1392 cm⁻¹.

¹ H-NMR (250 MHz, DMSO) δ1.11 (d, J=6 Hz, 3H, CH₃ CH), 2.72, 2.75 (s, 2H, H-1), 3.20 (dd, J=3 Hz, 6 Hz, 1H, H-6), 3.92 (m, 1H, H-5), 4.07 (m, 1H, CH₃ CH), 7.33 (d, J=6 Hz, 2H, 3,5-pyridyl-H), 8.44 (d, J=6 Hz, 2H, 2,6-pyridyl-H).

It is understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art. 

We claim:
 1. A compound of the formula ##STR176## in which R¹ represents hydrogen or represents an amino protective group,R² represents hydrogen, represents halogen, represents azido or phenyl, represents NHR¹, represents a radical of the formula ##STR177## represents straight-chain, branched or cyclic, saturated or unsaturated alkyl (up to C₆), which is optionally substituted by fluorine, chlorine or the group O--R⁸, X denoting sulphur or oxygen, R⁸ representing hydrogen, representing trimethylsilyl, triethylsilyl, triisopropylsilyl, tert.-butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, representing benzyl, benzyloxycarbonyl, 2- or 4-nitrobenzyl, 2- or 4-nitrobenzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, or representing formyl, acetyl, trichloroacetyl, trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2-(trimethylsilyl)-ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl, tetrahydropyranyl or benzoyl, R³ represents 3,4 -dimethoxyphenyl, represents chlorine, bromine, cyano, cyanato, azido, CF₃, represents --COR¹⁸, --CONR¹⁹ R¹⁸, allyloxycarbonyl, 4-nitrobenzylocxycarbonyl, --NHR¹⁸, ureido, guanidino, amidino, --NHSO₂ R²⁰, --OSO₂ R²⁰, --OPO(OR¹⁹) OR¹⁸, --S--R¹⁸, --SCOR¹⁸, --SO₂ OR¹⁸, --SO₂ NHR¹⁸, --SCN, --SO₂ R²⁰, --SCONH₂, --S--pyridyl, --S--pyrimidyl, --S--methyltetrazolyl, --S--thiadiazolyl, 2-aminothiadiazolyl or ##STR178## R¹⁸ and R¹⁹ being identical or different and representing hydrogen, representing straight-chain or branched alkyl (up to C₆), representing phenyl, 4-methylphenyl or benzyl, or representing a protective group for hydroxyl, mercapto or amino, and R²⁰ having the same meaning as R¹⁹ and R¹⁸ but not representing hydrogen or a protective group, and R⁴ represents hydrogen or represents methyl, ethyl, tert.-butyl, decyl, 2-chloroethyl, 2,2,2-trichloroethyl, cyanoethyl, diphenylmethyl or triphenylmethyl, acetonyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, tert.-butyldimethylsilyl, 1-phenoxyethyl or 2-methyl-2-propenyl, 4-nitrobenzyl, 2-nitrobenzyl, trimethylsilylethyl or dimethyl-tert.-butylsilylethyl or represents a radical of the formula ##STR179## --CH₂ --OCO--C(CH₃)₃, --CH(CH₃)OCOOC₂ H₅ or --CH₂ OCOCH₃.
 2. A compound according to claim 1, in whichR² represents hydrogen, chlorine, bromine, azido, NHR¹, a radical of the formula ##STR180## methyl, ethyl, i-propyl, tert.-butyl, ##STR181## R¹⁷ representing hydrogen, trimethylsilyl, tert.-butyldimethylsilyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert.-butoxycarbonyl, allyloxycarbonyl or formyl or acetyl.
 3. The compound 3-(tert.-butyldimethylsilyloxyethyl)-4-(3-allyoxycarbonyl-)-3-diazo-2-oxo-1-phenylpropyl)-azetidin-2-one of the formula ##STR182##
 4. A compound according to claim 1 wherein such compound is 3-(1-tert.-butyldimethylsilyloxyethyl)-4-(1-acetylthio-3-allyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one of the formula ##STR183## 